ARIZONA
BIOMEDICAL
RESEARCH
COMMISSION

2007 – 2008
Annual Report
January 2009

Arizona Biomedical Research Commission
Annual Report
2007–2008
Janet Napolitano, Governor
David Landrith, M.P.A., Chairman
COMMISSION MEMBERS
General Public
David Landrith, M.P.A.
David Jerman, M.B.A.
Gregorio M. Garcia, J.D.
Medical Community
Colleen Brophy, M.D.
Barbara Wuebbels, R.N., M.S.
Eve Shapiro, M.D.
Scientific Community
Manuel Modiano, M.D.
Thomas “Lon” Owen, Ph.D.
Joan Rankin Shapiro, Ph.D.

Staff
Executive Director: Dawn C. Schroeder, D.D.S., M.A.
Deputy Director: James Matthews, M.P.A.
Executive Staff Assistant: Damika D. Brock
Accountant II: Ismene Quintanilla
Program Project Specialist II: Daniel J. Powell
Administrative Assistant: Cecelia Tosie
15 South 15th Street, Suite 103A
Phoenix, Arizona 85007
Telephone: 602.542.1028
Fax: 602.542.6380
www.azabrc.gov
January 2009

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TABLE OF CONTENTS

Message from the Chairman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v
The Commission Members . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vii
General Public . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vii
Medical Community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ix
Scientific Research Community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .xi
Summary of 2007-2008 Commission Activities . . . . . . . . . . . . . . . . . . . . . . . . . .xiii

Section A: Continuing Contracts, Medical Research, Year Three, FY 2008 . . . . . . .1
Section B: Continuing Contracts, Medical Research, Year Two, FY 2008 . . . . . . .27
Section C: Continuing Contracts, Medical Research, Year One, FY 2008 . . . . . . .51
Section D: New Contract Awards, FY 2008 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .69
Section E: Indices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .105
Principal Investigator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .107
Subject . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109

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David Landrith, M.P.A.

Message from the Chairman
Medicine has changed in the 21st century. Life expectancy is the longest in the history of humankind.
The challenge of the 21st century is not to expand the length but to improve the quality of life by
preventing and defeating deadly and debilitating diseases. The Commission is supporting the Arizona
Parkinson’s Disease Center a significant neurological research project. The Commission supported at
a critical juncture the Arizona scorpion anti-venom project. The Commission continues to support an
innovative approach to decrease the amount of scar tissues after heart attack. The Commission also
supports a personalized approach to cancer therapy. These programs as well as efforts designed to
support individual researchers are core to the mission of the Commission.
The Commission awarded nineteen new scientific research contracts this year. There will be a total of
seventy-four research projects under contract with the Commission beginning in FY2009. The Annual
Report contains abstracts of all the projects along with information on funding levels and institutional
involvement. The abstracts demonstrate the wide breadth of inquiry being undertaken by Arizona
investigators. Commission contract awards enabled many Arizona researchers to prove their investigative
concepts and go on to obtain additional funding at the national level. The Commission through its
statutory authority continues its technology transfer efforts.

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The Commission continued to work in cooperation with the Flinn Foundation to move the
recommendations of the Arizona Bioscience Roadmap forward. The Commission has taken the lead
in accomplishing the translational research goals. Commission sponsored researchers are pursuing
translational research in the neurosciences, cancer, bioengineering, and bioimaging. Of particular note
is the progress being made in innovative approaches to research in Native American communities. The
Commission created and continues to support the Arizona Translational Resource Network. AzTransNet
is focused on removing institutional barriers to research, for example, establishing statewide or community
based Institutional Review Boards; developing collaborative associations and clinical research networks;
and providing streamlined business practice templates such as uniform intellectual property contract
documents and material transfer agreements.
The Commission is undergoing the ten-year sunset audit review process. The Commission thanks the
Office of the Auditor General for the time and effort they spent in learning about the work of the
Commission. The audit recommendations are timely and useful. The Commission is adopting all of
the recommendations.
The Annual Report is prepared and submitted each year to the Governor, the President of the Senate,
the Speaker of the House of Representatives. It is the hope of all of the members of the Arizona
Biomedical Research Commission that encouraging both new researchers and large scale multiinstitutional/multidisciplinary investigation will advance scientific discovery in the search for better
health and lives of all Arizonans.

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The Commission Members
Nine Commissioners guide the work of the Arizona Disease Control Research Commission. They are
appointed by the Governor and confirmed by the Senate. The Commission is divided into three
communities—General Public, Medical, and Scientific Research. Each community is represented by
three Commissioners appointed for three-year terms. Generally, the terms of three members expire each
year; Commissioners may be reappointed. The Chairman and Commissioners who served during
2005–2006 are presented below.

General Public
Gregorio M. Garcia, Esq.
Shughart, Thomson & Kilroy, P.C.
Commissioner Garcia received his undergraduate and graduate
degrees from Arizona State University. He holds a Juris Doctorate
and Master of Business Administration. He is currently pursuing
a Master of Laws (LL.M.) in Biotechnology and Genomics.
Commissioner Garcia is an attorney and practices with the firm
of Shughart, Thomson & Kilroy, P.C. He sits on the board of
directors for Arizona’s largest legal aid law firm, Community
Legal Services, and has held leadership positions within the
State Bar of Arizona and other legal organizations. Commissioner
Garcia was appointed by Governor Napolitano in 2006.

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David Jerman, M.B.A.
Administrative Director
Arizona Alzheimer’s Research Center and Arizona Alzheimer’s Disease Institute
Commissioner Jerman received his undergraduate accounting
and Masters of Business Administration in finance degrees from
the University of Utah. He has extensive experience in the
pharmaceutical industry and in technology transfer issues.
Commissioner Jerman is the Administrative Director of the
Arizona Alzheimer’s Disease Institute located within Banner
Healthcare system. The Arizona Alzheimer’s Research Center is
a statewide research consortium composed of ASU, UA, TGen,
Banner, Mayo Clinic Scottsdale, Sun Health Research Institute,
and Barrow Neurological Institute. Commissioner Jerman is
also Chairman of the Board of Directors of Frontier Scientific
Incorporated. Jerman was appointed by Governor Napolitano in 2005.

David Landrith, M.P.A.
Vice President of Policy and Political Affairs, Arizona Medical Association
Commissioner Landrith is the Vice President of Policy and
Political Affairs at the Arizona Medical Association. His
undergraduate studies were in political science at Arizona State
University. He received a Masters of Public Administration
degree at Harvard University and accomplished summer studies
at Oxford. Commissioner Landrith is the Chairman of the
Board of Arizona Health-e Connection and serves on the steering
committee of The Arizona Partnership for Immunization. He
has served as co-chairman of the ASU Dean’s Advisory Council,
a member of the Arizona Town Hall Board of Directors, member
of the ST. Vincent De Paul Free Medical and Dental Clinic
Endowment Committee, Director of the Arizona Bioethics Network, and Past Chairman and Executive
Secretary of the Arizona Council of Governments Directors’ Association. He has received the Partnership
Award from the Arizona Chapter of the American Academy of Pediatrics, and the Presidential Award
for the Arizona State Association of Physician’s Assistants. Commissioner Landrith was appointed by
Governor Napolitano in 2004. His term expired in 2007, and he was re-appointed by Governor
Napolitano in 2008.

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Medical Community
Colleen Brophy, M.D.
Chief of Vascular Surgery
Carl T. Hayden VAMC
Dr. Brophy is a vascular surgeon, scientist, and entrepreneur.
She is currently Research Professor of Kinesiology at the Center
for Metabolic Biology, Adjunct Professor of Bioengineering,
and Adjunct Professor of Cellular and Molecular Biology, Arizona
State University; Chief of Vascular Surgery at the Carl T. Hayden
VA Medical Center in Phoenix; and a Clinical Professor of
Surgery at the University of Arizona. Brophy received both her
B.S. and M.D. from the University of Utah. She was a surgical
resident at Yale University and a vascular fellow at Harvard
University. She has received the National Institutes of Health
(NIH) National Research Service Award; the American College
of Surgeons Faculty Fellowship Award; the SVS/ISCVS Lifeline Foundation Award; the Clinician
Scientist Award from the American Heart Association and the Von Leibig Foundation Award for EarlyCareer Academic Surgeons, for her investigative research. She has been continuously supported by the
NIH and VA (Merit Award) for over 15 years. She has over 70 publications in peer reviewed journals
and has edited a textbook in vascular surgery. Dr. Brophy has served on the Executive Councils for
the Association of Academic Surgery, Society of University Surgeons, and the Lifeline Foundation
Board of Directors. She is an associate editor for the Journal of Surgical Research and has served on
the editorial board of Surgery. She served as an active member of the Bioengineering, Biotechnology,
and Surgical Sciences (BTSS) and the Cardiovascular Devices (SBTS) study sections of the NIH. She
is currently serving on the Executive Committee of the Surgical Research Committee of the American
College of Surgeons and was recently appointed Chair of this committee. Dr. Brophy is the Chair of
the Young Surgical Investigators course for the American College of Surgeons. She has been Chair of
the Committee on Women’s Issues for the Society for Vascular Surgery. She was appointed in 2002
and 2006 by Governor Napolitano.

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Barbara Wuebbels, R.N., M.S.
Director of Clinical Education
BioMarin Corporation
Commissioner Wuebbels received her Bachelor of Science in
Nursing from St. Louis University, her Master of Science in
Business Administration from the University of Phoenix, and
her Master of Science in Adult Health Nursing from Arizona
State University. Prior to joining BioMarin, she served as Director
of Clinical Education at Medicis Pharmaceutical Corporation,
as research coordinator at Maricopa Medical Center, and as
Director of Clinical Affairs at Vivra Health Advantage in
Brentwood, Tennessee. Commissioner Wuebbels has presented
at various national conferences and she has published on nursing
research, spinal cord stimulation, and wound care in the long
term care setting. Wuebbels was appointed by Commissioner Napolitano in 2006.

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Scientific Research Community
Manuel Modiano, M.D.
Arizona Oncology Associates
Commissioner Modiano obtained his Bachelor of Science degree
from Colegio Collumbia in Mexico City. He received his M.D.
with high honors from the Universidad Nacional Autonoma
de Mexico. He completed post graduate education at the
University of Wisconsin, Mount Sinai Medical Center, and the
University of Arizona – Arizona Cancer Center. Commissioner
Modiano has published numerous peer reviewed articles and
has served as Principal Investigator in numerous clinical research
studies. Dr. Modiano is Director of Research for Arizona
Oncology Associates, Medical Director of the Arizona Clinical
Research Center, Past Chief of Hematology and Oncology and
Past-President of the Medical Staff at Carondelet St. Mary’s Hospital and Medical Center, and Past
President of the Arizona Clinical Oncology Society. He was appointed by Governor Napolitano in 2006.

T. Lon Owen, Ph.D.
Professor of Medical Anatomy and Physiology
Northern Arizona University
Commissioner Owen received his B.A. in Zoology from the
University of California, a Master’s Degree in Biology from
California State University at Sacramento, and his Ph.D. in
Physiology from U.C. Davis. He was an NIH Postdoctoral
Fellow at Michigan State University and Visiting Associate
Professor in the Pharmacology Department of the University
of Arizona College of Medicine. He is a member of the American
Physiological Society and has chaired the Research Committees
of the American Heart Association at both the Arizona Affiliate
and Southwestern Regional levels. His publications are in the
areas of cardiovascular, aging, and environmental physiology. He
has taught physiology and pathology at Northern Arizona University since 1974. He is a member of
the Translational Genomics Research Institute Board of Directors. Commissioner Owen was appointed
to the Commission by Governor Hull in 1998 and 2001. His term expired in 2004, and he was
reappointed by Governor Napolitano in 2006.

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Joan Rankin Shapiro, Ph.D.
St. Joseph’s Hospital and Medical Center
Commissioner Joan Rankin Shapiro is a human geneticist who
received her M.D., Ph.D. from Cornell University Medical
College in 1979. Her initial research was in human birth defects
at Rockefeller University. She began her cancer career at
Memorial Sloan-Kettering Cancer Center, New York. In
September,1989, she relocated to the Barrow Neurological
Institute (BNI) of St. Joseph’s Hospital and Medical Center,
Phoenix, Arizona, where she became the Director of NeuroOncology Research. Her research involved the characterization
of genetic abnormalities associated with central nervous system
malignancies. Since 1979 her grant awards have totaled more
than fourteen million dollars. In November 2007 she received a Life Time Achievement Award from
the Society of Neuro-Oncology for her contribution to the field. She served thirteen years as an NIH
Reviewer on Pathology A and on Experimental Therapeutics study sections. In 2001 Dr. Shapiro
retired from the laboratory and has assumed the role as V.P., Research and Development at St. Joseph’s
Hospital and Medical Center. She is the Past President of the National Organization Women in Cancer
Research. Dr. Shapiro has also retained a strong commitment to community education. She has
developed and continues to teach numerous school enrichment programs. In conjunction with the
American Academy of Neurology, she conducted K-12th grade neuroscience enrichment training
workshops for physicians and scientists. She is the past Chairman of the National Neuroscience prize
for high school students. She remains at St. Joseph’s Hospital and Medical Center as a Consultant for
research activities. She was appointed by Governor Napolitano in 2007.

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Summary of 2007–2008 Commission Activities
In the fiscal year 2007-2008, Arizona biomedical researchers received more than $7 million in 74
contracts administered by the Commission. The Commission continued its commitment to individual
investigators, investigator collaborations, and further expansion into translational research. 19 new
contracts and approximately $1.7 million from the Health Research Fund and the Disease Control
Research Fund were directed toward assisting individual investigators in developing proof of their
research concepts, collecting preliminary data, and in continued support of translational research.
Section headings in this report list each program and whether the project is in its first, second, or third
year of funding. Research abstracts outlining the progress made during the year are contained in
Sections A-C. Citations for 170 scientific publications, abstracts, and presentations arising out of the
research are also listed. Section D provides information on new contracts awarded beginning July 1,
2008 (FY2009).
Over 1,000 Requests for Proposals (RFPs) for the 2007-2008 awards were mailed to potential applicants
in September 2006. The Commission has seen a decrease in revenue available from the sale of tobacco
products which in turn decreased the amount of funding for new biomedical research to approximately
$1.2 million. The decline may be attributed to the impact of the Early Childhood Development and
Health Initiative adopted by the voters and effective starting in January of 2007. The initiative earmarked
tobacco funds for the Childhood Development and Health program and reduced the availability of
funds for the ABRC compared to previous years.

While revenue from the tax on tobacco sales fell during the fiscal year, revenue from the proceeds of
the State Lottery remained consistent with the previous fiscal year. Lottery revenue in Fiscal Year 2007
was $2.4 million and in Fiscal Year 2008 it was $2.5 million.

xiii

In response to the RFP, the Commission received 131 unrestricted medical research proposals. In
November and December the medical research proposals were sent to a panel of national and international
scientific and medical experts for peer review and evaluation. The Commission received the proposal
evaluations prepared by more than 170 out-of-state peer reviewers. Three reviews were sought for each
proposal. In the spring and summer of 2007 the Commission selected 19 proposals for funding.
ABRC Projects Submitted/Accepted FY 2008
(Health Research Fund and Disease Control Research Fund)
Institution
Arizona State University
Northern Arizona University
St. Joseph’s Hospital
Sun Health Research Institute
TGen
University of Arizona
Others
Total

Submitted

Accepted

23
2
10
6
7
77
5
131

3
1
1
0
1
13
0
19

Percent
Accepted
12
50
10
0
14
17
0
15

Amount
$
350,000
300,000
50,000
0
150,000
850,000
0
1,700,000

Percent of
Total $
20
18
3
0
9
50
0
100

During 2007-2008 the ABRC managed a total of 74 translational and biomedical research projects
representing eight research institutions.
ABRC Total New and Continuing Project Contracts 2008
Institution

Awarded

Arizona State University
Inter Tribal Council of Arizona
Mayo Clinic Scottsdale
Northern Arizona University
Sun Health Research Institute
St. Joseph’s Hospital
TGen
University of Arizona
Total

xiv

7
1
2
3
5
7
4
45
74

% of Total
Awarded
10
1
2
4
7
10
5
61
100

In June of 2008 the Commission awarded 28 new research contracts for a total of approximately $1.3
from all sources. The contracts were effective on July 1, 2008. Progress on these projects will be reported
in the next Commission Annual Report.
ABRC Projects Submitted/Accepted FY 2009
Institution
ASU
St. Josephs
TGen
UA
All Others
Total

Submitted

Accepted

22
21
2
70
9
124

6
7
1
14
0
28

Percent
Submitted
18
17
2
56
7
100%

Percent
Awarded
21
25
4
50
0
23

$ Amount
Awarded
297,705
347,572
50,000
648,801
0
$1,344,078

Percent of
Total $
23
25
3
49
0
100%

The Commission remains committed to making the results of scientific discovery more readily available
to health care providers and then to patients. The Commission currently has 15 translational projects
underway. The Commission has sponsored workshops and symposia examining translational issues such
as the appropriate treatment of biospecimens. Institutional barriers are being addressed by the Commission
sponsored Arizona Translational Resource Network (AzTransNet). Workshops, model documents, and
consulting services relating to Institutional Review Boards, collaborative agreements, intellectual property
contracts, and clinical trial networks have been developed and delivered by AzTransNet. The Commission
is confident that these translational projects will result in more rapid deployment of medical therapies
to Arizonans.
The Commission’s matching fund program has been well received by researchers and their home
institutions. Growing from the initial three research programs, the Commission is managing research
contracts for seven projects. In each of the programs the Commission investment is matched dollar
for dollar by the sponsoring institutions. In order to be eligible for the matching fund program the
research project must be multi-disciplinary, inter-institutional, and collaborative. The goals are to
promote cooperation among researchers and between institutions, and to tackle significant biomedical
research issues. In every project there are more than one principal investigator, more than one institution,
and multiple research hypotheses.

xv

Jointly Funded Research Projects
Project Title
Arizona Parkinson’s Disease Center
Scorpion Treatment and Imaging of Neurotoxicity Group
Multimeric Ligands for Targeting Cancer for Imaging and Therapy
Drug Targeting the i-Motif in the c-MYC Promoter
Biomimetic Scaffolds for Spinal Cord Regeneration
Modeling Vulnerability of Cancer
Translational Research on AB Metabolism from Synthesis to Clearance

Home Inst 3-yr Amt
Mayo
$ 750,000
UA
540,553
UA
750,000
UA
517,500
BNI
750,000
NAU
414,768
SHRI
675,000

One measure of research success is the publication of research findings in a recognized peer reviewed
scientific publication. In 2007-08 ABRC sponsored researchers reported 147 publications, abstracts,
and presentations of their research findings. Publication of scientific findings is a critical step in the
research enterprise. The data reported provides the foundation upon which the next research project
is founded. It is through this iterative process than scientific discovery takes place.
During the Annual Report period fiscal year 2007-2008, 223 full time and part-time jobs were created
including principal investigators.
If a scientific discovery has the potential for commercial application, it is important that the rights to
that discovery be protected. The Commission on behalf of the citizens of Arizona holds seven patents
on biomedical compounds with potential commercial value.
Five Rose, et al patents are focused on technologies that will increase the effectiveness of cancer
chemotherapy drugs by reducing the ability of cancer cells to expel the drugs from the host cell.
Two Gervay-Hague patents are for drugs that block the incorporation of tumor cell markers into cancer
cells. These drugs may help stop the spread of cancer in the human body.
One Schroeder patent relates to methods of inhibiting, retarding, and reducing metastatic cancer
growth.

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TGen the Translational Genomics Research Institute
The ABRC through a contract provides funding to support the basic operational infrastructure of
TGen, the Translational Genomics Research Institute. TGen is on the cutting edge of translational
research where investigators are able to unravel the genetic components of common and complex
diseases.
TGen is pursuing research on oncology, diabetes and heart disease, and neurological disease. All of
these disease areas are of extreme importance to Arizona citizens.
Some TGen activities include:
• Developing a $200 million program funded by the Luxembourg government to develop a biobanking
and biotechnology initiative in Luxembourg.
• A project to address the disproportionate impact of renal cell carcinoma in the Salt River PimaMaricopa Indian Community with a study conducted in collaboration with the members of the
community.
• The Partnership for Personalized Medicine which is a $45 million program designed to make
personalized medicine a reality. Funding comes from the Virginia G. Piper Charitable Trust and
the Flinn Foundation. The initiative is headed by 2001 Nobel Laureate Dr. Lee Hartwell.
• A team of researchers who are conducting a genomic study of autism, a disease which touches 1 in
150 children in Arizona.
TGen researchers:
• Have published more than 80 scholarly articles in peer-reviewed academic journals.
• Are conducting nearly 30 clinical trials for advanced and/or rare cancers.
• Have submitted 127 grant requests receiving 24 awarded grants in excess of $10.2 million; 39 grant
applications totaling over $24.3 are pending peer review.
• The success rate of 24 percent of total grants submitted nearly doubles the national average of 13
percent.
TGen enterprise and collaborative efforts:
• 25 invention disclosures have been filed in FY08. Disclosure is the first step toward protecting
intellectual property via the patent process.
• 97 confidential disclosure agreements have been signed in FY08. Confidential disclosure agreements
are one measure of collaboration between TGen and the research community.
• 51 material transfer agreements between TGen researchers and other collaborators have been signed
in FY08.
• 38 research collaborations have been signed in FY08 including agreements with research institutes
and hospitals around the world.

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TGen job creation:
• There are 270 full-time TGen employees with 80 percent holding a college degree
• 39 new full-time equivalent positions were created in FY08 with pay and benefits totalling
approximately $1,862,000.
• 58 high school, undergraduate, and graduate interns had part-time employment with TGen
in FY08.
The energy and focus of TGen leadership and researchers is rapidly advancing collaborative, multiinstitutional, interdisciplinary research in Arizona. The financial infrastructure support provided by
the Arizona Biomedical Research Commission makes these things possible. The Commission is
encouraged by the efforts of TGen, and heartened by the impact that TGen research is making in
biomedical research.

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Section A
Continuing Contracts
Medical Research
Year Three
FY 2008

1

2

Charles H. Adler, M.D., Ph.D.

Mayo Clinic Scottsdale
Award Amount FY 2008: $250,000

Arizona Parkinson’s Disease Center: Prevention of Progression to Parkinson’s Disease and
Parkinson’s Disease with Dementia: Development of Biomarkers and Novel Treatment Strategies
The APDC is working on clinical biomarkers and novel treatment strategies for Parkinson’s disease
and PD with dementia (PDD). There is a clinical core, which prospectively examines PD and control
subjects enrolled in the brain and body donation program, and a neuropathology core that performs
the autopsies and provides CSF and brain tissue to the laboratory scientists. To date >5,000 clinical
evaluations of >1,000 subjects have occurred. In the past year 22 parkinsonism (11 PD) and 16 control
subjects were autopsied. Projects 1 and 2 have found changes in BDNF, α-synuclein, and DJ-1 proteins
in PD. Project 3 found dysregulation of multiple sets of genes in PD and PDD while Project 4 found
differences in cerebrospinal fluid proteins in PDD. Stated goals have been met. In the past year 15
papers were published, 10 are in process, and 5 presentations were made. Funding was received from
the Michael J. Fox Foundation and the National Parkinson’s Foundation.
Beach TG, Sue LI, Walker DG, Lue L-F, Connor DJ, Caviness JN, Sabbagh MN, Adler CH. Marked
Microglial Reaction in Normal Aging Human Substantia Nigra: Correlation with Extraneuronal
Neuromelanin Pigment Deposits. Acta Neuropathol. 114:419-24. 2007.
Beach TG. Sue LI, Walker DG, Roher AE, Lue L-F, Vedders L, Connor DJ, Sabbagh M, Rogers J.
The Sun Health Research Institute Brain Donation Program: Description and Experience, 1987-2007.
Cell & Tissue Banking. 9:229-45. 2008.
Beach TG, Adler CH, Sue LI, Peirce JB, Bachalakuri J, Dalsing-Hernandez JE, Lue L-F, Caviness JN,
Connor DJ, Sabbagh MN and Walker DG. Reduced Striatal Tyrosine Hydroxylase in Incidental Lewy
Body Disease. Acta Neuropathol. 115:445-51. 2008.
Beach TG, White CL, Hamilton RL et al. Evaluation of α-synuclein Immunohistochemical Methods
Used by Invited Experts. Acta Neuropathol. 116:277-88. 2008.
Beach TG, White CL, Hladik CL, Sabbagh MN, Connor DJ, Caviness JN, Sue LI, Sasse J, Bachalakuri
J, Akiyama H, Adler CH. High Specificity and Sensitivity of Olfactory Bulb Synucleinopathy for Lewy
Body Disorders. J Neuropathol Exp Neurol. 67:489. 2008.
Bychkov ER, Gurevich VV, Joyce JN, Benovic JL, Gurevich EV. Arrestins and Two Receptor Kinases
are Upregulated in Parkinson’s Disease with Dementia. Neurobiol Aging. 29(3):379-96. 2008.

3

Caviness JN, Driver-Dunckley ED, Sabbagh MN, Connor DJ, Noble B, Evidente VGH, Shill H,
Adler CH. Defining mild cognitive impairment in Parkinson’s Disease (PD-MCI). Mov Disorders.
22:1272-7. 2007.
Caviness JN, Hentz JG, Evidente VGH, Driver-Dunckley ED, Samanta J, Mahant P, Connor DJ,
Sabbagh MN, Shill HA, Adler CH. Both Early and Late Cognitive Dysfunction Affects the
Electroencephalogram in Parkinson’s Disease. Parkinsonism and Related Disorders. 13:348-54. 2007.
Sabbagh MN, Lahti T, Connor DJ, Caviness JN, Shill H, Mahant P, Samanta J, Burns RS, Evidente
VGH, Driver-Dunckley ED, Reisberg B, Bircea S, Adler CH. Functional Decline Correlates with
Cognitive Impairment in Alzheimer’s Disease and Parkinson’s Disease. Dement Geriatr Cogn Disord.
24:327-34. 2007.
Sabbagh MN, Adler CH, Lahti TJ, Connor DJ, Peterson LK, Caviness JN, Shill HA, Sue LI, Ziabreva
I, Perry E, Ballard CG, Aarsland D, Reid RT, Walker DG, Beach TG. Parkinson’s Disease with Dementia:
Comparing Patients with and without Alzheimer’s Disease Pathology. Alz Dis Assoc Disorders. In
press.
Sabbagh MN, Sandhu SS, Farlow MR, Beach TG, Vedders L, Shill HA, Caviness JN, Connor DJ,
Sue L, Adler CH. Correlation of Clinical Features to Argyrophilic Grains at Autopsy. Alz Dis Assoc
Disorders. In press.
Shill HA, Adler CH, Sabbagh MN, Connor DJ, Caviness JN, Hentz JG, Beach TG. Pathological
Findings in Prospectively Ascertained Essential Tremor Subjects. Neurology. 70:1452-5. 2008.
Sparks DL, Ziolkowski C, Connor D, Beach TG, Adler C, Sabbagh M. Copper and Cognition in
Alzheimer’s Disease and Parkinson’s Disease. Cell Biol Toxicol. 24:423-30. 2008.
Stamper C, Siegel A, Liang WS, Pearson JV, Stephan DA, Shill H, Connor D, Caviness JN, Sabbagh
M, Beach TG, Adler CH, Dunckley T. Neuronal Gene Expression Correlates of Parkinson’s Disease
with Dementia. Mov Disord. 23(11):1588-95. 2008.
Ye, L, Velasco A, Fraser G, Beach TG et al. In vitro High Affinity α-synuclein Binding Sites for the
Amyloid Imaging Agent PIB are Not Matched by Binding to Lewy Bodies in Postmortem Human
Brain. J Neurochem. 105:1428-37. 2008.
Adler C, Connor D, Sabbagh M, Caviness J, Shill H, Hentz J, Beach TG. Non-specific Motor and
Cognitive Changes in Incidental Lewy Body Disease. Neurol. 70(Suppl 1):A287. 2008.

4

Adler CH, Connor DJ, Sabbagh MN, Shill HA, Hentz JG, Evidente VGH, Mahant P, Samanta J,
Burns RS, Ahmed A, Driver-Dunckley ED, Vedders L, Noble B, Caviness JN. Parkinson’s Disease
Increases the Risk for Developing Mild Cognitive Impairment. Mov Disorders. 23(Suppl 1):S100. 2008.
Adler C, Connor D, Sabbagh M, Beach TG, Shill H, Vedders L, Sue LI, Caviness J. Neuropathologic
Findings in Patients with Parkinson’s Disease and Mild Cognitive Impairment. J Neurol. 255 (Suppl
2):31-2. 2008.
Beach TG, Connor DJ, Sue LI, Caviness JN, Sabbagh MN, Adler CH. Motor and Cognitive Findings
in Incidental Lewy Body Disease. J Neuropathol Exp Neurol. 66(5):422. 2007.
Beach TG, Walker DG, Lue L-F, Sue LI, Sasse J, Bachalakuri J, Watson J, Boyer S, Shirohi S, Peirce
J, Brooks R, Sabbagh M, Hentz J, Shill H, Connor D, Adler C. Incidental Lewy Body Disease:
Prevalence, Neuropathology, Biochemical Correlates, and Clinical Profile. Arizona Alzheimer’s Annual
Consortium Meeting. Phoenix, AZ. 2008.
Beach TG, White CL, Hladik C, Sabbagh MN, Connor DJ, Caviness JN, Sue LI, Sasse J, Bachalakuri
J, Akiyama H, Adler CH. High Specificity and Sensitivity of Olfactory Bulb Synucleinopathy for Lewy
Body Disorders. Am Assoc Neuropathologists. 2008.
Benson BV, Sabbagh M, Adler C, Hentz J, Sue LI, Shill H, Caviness J, Dalsing-Hernandez JE, Walker
DG, Lue L-F, Vedders L, Lahti T, Beach TG. Parkinson’s Disease and Apolipoprotein E. Neurol.
70(Suppl 1):A326. 2008.
Sabbagh MN, Sandhu SS, Farlow M, Beach TG, Vedders L, Shill HA, Caviness JN, Connor DJ,
Sue LI, Adler CH. Correlation of Clinical Features to Argylophilic Grains at Autopsy. Neurol.
70(Suppl 1):A118. 2008.

5

Leslie Boyer, M.D.

University of Arizona
Award Amount FY08: $188,526

Scorpion Treatment and Imaging of Neurotoxicity Group (STING)
Neurotoxicity from scorpion sting is rare, but it may be life-threatening, especially in young children.
This study addresses: 1) the shortage of an effective treatment for severe scorpion neurotoxicity, and
2) the lack of a validated clinical assessment tool with which to further new drug development and
train emergency providers. Since the start of this project, a total of 21 rural and urban hospitals in
Arizona have joined the study network and have treated over 548 patients, ranging in age from 25
days to 80 years. Digital video images of patients and of age-matched controls have been collected for
development of a medical training tool. This project has resulted in shorter hospital stays, fewer
admissions to the Pediatric and Adult Intensive Care Units, and increased safety for children and adults
stung and treated in Arizona.
Boyer LV, Alagon A, Mallie J. Efficacy and Safety of a F(ab’)2 Antivenon for Scorpion Envenomation.
Venom Week. Tucson, AZ. 2007.
Boyer LV, Mallie J, Chase PB, Theodorou A. Neurotoxicity in Children Hospitalized Due to North
American Scorpion Envenomation. Venom Week. Tucson, AZ. 2007.
Boyer LV. Clinical Trials of Scorpion Antivenom. Venom Week. Tucson, AZ. 2007.
Ruha M. The Phoenix Experience. Venom Week. Tucson, AZ. 2007.
Fox F. Challenges of Treating Scorpion Envenomation in a Neonate in a Rural Setting. Venom Week.
Tucson, AZ. 2007.

6

Thomas Bunch, Ph.D.

University of Arizona
Award Amount FY08: $49,997

A Rapid and Inexpensive Screen for Mutations that Sensitize Cells to Cancer Drugs
The primary goal has been to develop a system that can identify specific genetic lesions that sensitize
cells to the effects of particular anti-cancer drugs. This system takes advantage of the ease with which
individual genes can be neutralized in cells from the fruit fly, Drosophila. In year one we established
procedures for eliminating hundreds of genes, one at a time, and asking if this sensitizes cells to die
when drug is added. In year two we tested 3 compounds that target pathways that potentially promote
abnormal cell growth or survival in tumor cells. Numerous novel interactions have been uncovered,
and in year three we have worked to validate these finding in human tumor cell lines. Additionally,
we have completed new screens that involved 5 additional cancer therapeutic drugs as well as ionizing
radiation. Interactions have been discovered in all of these screens and are now being validated.
Diep C.H., Bunch T, Kendall T, Mukai L, Straus S, Munoz RM, Han H, Brower D,Von Hoff D.
Identification of Chemosensitizing Gene Targets Using a Drosophila Cell-based RNAi Screen. American
Association for Cancer Research. San Diego, CA. 2008.

7

Johanna DiStefano, Ph.D.

TGEN
Award Amount FY08: $50,000

Diabetic Kidney Disease in American Indians
Diabetic kidney disease is caused by genetic and environmental factors, and previous microsatellite
genotyping has shown that linkage for diabetic nephropathy in Pima Indians is centered on an interval
of approximately 40 cM on chromosome 3q. We genotyped 17 additonal markers on 3q and reevaluated
the evidence for linkage. We estimated LOD scores of 1.94 using the mean IBD method and 2.63
using the scoring method. To further narrow the region of linkage, we genotyped 359 SNPS between
markers D3S1763 and D3S3041 in Pima families with diabetic nephropathy and individuals with
end-stage renal disease (ESRD) caused by type 2 diabetes. However, results from the additional saturation
genotyping on 3q did not significantly narrow the region of linkage, nor did we observe an increase
in the evidence for linkage in this area. Analyses defined two peaks, the highest peak having a LOD
score of 1.5 and the corresponding SNPs under this peak lie within the inactive N-acetylated-alphalinked acidic dipeptidase-like protein 2 (NAALADL2) gene. In conjunction with this approach, we
also genotyped nine markers in the candidate gene, SUCNR1, that were prviously shown to be
significantly associated with type 2 diabetic ESRD in Pima Indians, in a study sample comprised of
Caucasians with ESRD attributed to type 1 diabetes. None of these markers showed evidence for
association at levels that reached statistical significance in this study sample suggesting that different
variants underlie susceptibility to ESRD in diabetes in these independent study samples. Future studies
include further investigation of genes under the linkage peak, including NAALADL2, as well as other
genes that may have a biological effect on the progression of diabetic kidney disease. Preliminary
analyses of the associated SUCNR1 SNPs in the Pima population indicated that these mutations may
influence the binding efficiencies of two transcription factors. We plan to investigate these SNPs further
to see they impact the function of this gene.

8

David Duggan, Ph.D.

TGEN
Award Amount FY08: $50,000

Genetic Basis of Auricular-Condylar Syndrome in Two AZ Families
Auriculo-condylar syndrome (ACS) is a disorder characterized by congenital ear, jaw, temporomandibular
joint and other abnormalities. By studying two Arizona families, our goal is to determine the genetic
basis of ACS. In years 1 and 2, a disease-causing region in the human genome had been localized to
chromosome 20 and a candidate disease-causing gene re-sequenced. Four novel DNA sequence variants
were identified. Unfortunately, further testing of the identified and putative disease-causing changes
revealed that they were not the causative changes. In this final year (year 3), we have begun to make
use of the latest in state-of-the-art genetic technologies that allows a more thorough examination of
the candidate disease-causing gene(s). Using next generation re-sequencing technologies and costefficient approaches developed by the TGen scientists, we intend to re-sequence the entire candidate
disease-causing gene found on chromosome 20. For cost reasons associated with earlier re-sequencing
technologies, only the protein coding regions of the DNA were re-sequenced in year 2 and only in a
subset of the family members. This year, the entire gene including protein-coding, protein non-coding,
and DNA sequences up- and down-stream of this gene will be sequenced. Such an approach has a
high likelihood of identifying the disease-causing genetic change(s) in these two Arizona families.

9

Katerina Dvorak, Ph.D.

University of Arizona
Award Amount FY08: $153,922

Barrett’s Esophagus Esophageal Adenocarcinoma and Apoptosis
Barrett’s esophagus (BE) is an esophageal lesion that arises as a consequence of chronic heartburn. BE
is often associated with esophageal adenocarcinoma. More than one hundred patients will die of this
cancer in Arizona in 2008 based on death rates in prior years. The mechanism of development of BE
is poorly understood. Gastric acids, secreted from the stomach, and bile acids, secreted in response to
a high fat diet, are implicated in the development of BE. We found that bile acids and gastric acid
induce oxidative damage, abnormal cellular signaling, and mutations, which may lead to cancer.
However these processes can be reversed by the replacement of bile acids with a special, protective bile
acid, glycoursodeoxycholic acid, that is commonly used to treat liver diseases. An understanding of
the development and progression of BE to esophageal carcinoma is crucial for the design of targeted
strategies to prevent and eradicate this cancer.
Dvorak K, Payne CM, Chavarria M, Ramsey L, Dvorakova B, Bernstein H, Holubec H, Sampliner
RE, Guy N, Bernstein C, Green SB, Prasad A, Garewal HS. Bile Acids in Combination with Low pH
Induce Oxidative Stress and Oxidative DNA Damage: Relevance to the Pathogenesis of Barrett’s
Oesophagus. Gut. June. 56(6): 763-71. 2007.
Dvorak K, Chavarria M, Payne CM, Ramsey L, Dvorakova B, Dvorak B, Bernstein H, Holubec H,
Sampliner RE, Bernstein C, Prasad A, Green SB, Garewal HS. Activation of the IL-6/STAT3 Antiapoptotic Pathway in Esophageal Cells by Bile Acids and Low pH: Relevance to Barrett’s Esophagus.
Clinical Cancer Research. Sept. 15; 13(18): 5305-13. 2007.
Bernstein C, Payne CM, Dvorak K, Bernstein H. Role of Bile Acids in Gastrointestinal Carcinogenesis.
US Gastroenterology and Hepatology Review. In press.
Bernstein C, Bernstein H, Payne CM, Dvorak K, Garewal H. Field Defects in Progression to
Gastrointestinal Tract Cancers. Cancer Letters. Dec. 28, 2007. Epub ahead of print.
Dvorak K, Watts GS, Ramsey L, Holubec H, Payne CM, Bernstein C, Jenkins GJ, Sampliner R, Prasad
A, Garewal H, Bernstein H. Expression of Bile Acid Transporting Proteins in Barrett’s Esophagus and
Esophageal Adenocarcinoma. American Journal of Gastroenterology. In press.
Payne CM, Crowley-Skillicorn C, Holubec H, Dvorak K, Bernstein C, Moyer MP, Garewal H, Bernstein
H. Deoxycholate Induces the Autophagic Stress-Survival Pathway: Implications for Colon Carcinogenesis.
European Journal of Nutrition. Submitted.

10

Bernstein C, Payne CM, Dvorak K, Bernstein H. Role of Bile Acids in Gastrointestinal Carcinogenesis.
US Gastroenterology and Hepatology Review. In press.
Payne CM, Bernstein C, Dvorak K, Bernstein H. Hydrophobic Bile Acid, Genomic Instability,
Darwinian Selection and Colon Carcinogenesis. Clinical and Experimental Gastroenterology. Submitted.

Mohamed A. Gaballa, Ph.D.

Sun Health Research Institute
Award Amount FY08: $50,000

Human Umbilical Progenitor Cell Based Therapy for Myocardial Infarction
Intramycocaridal and intravenous delivery of human umbilical cord blood cells (hUCBCs) improves
vascularization (the number of blood vessels) and heart function after myocardial infarction (M, heart
attack). The effects of intracoronary delivery of hUCBCs on vasculogenesis induction and its mechanisms
in the ischemia-reperfusion model remain unclear. Ischemia was produced in immune compromised
rats by ligation of the left anterior coronary artery for 60 minutes, followed by reperfusion with either
150 µl of media containing one million stem cells or media only. Animals were studied three weeks
later. Compared to media only, left heart muscle contractile pressure increased and left heart size was
decreased in animals treated with stem cells. The improvement in heart function is more likely due to
the increase in the number of new blood vessels after stem cell delivery. In conclusion, intracoronary
delivery of hUCBCs improved heart function after an acute heart attack. The improvement was due
to the generation of de novo blood vessels. No significant number of newly-formed cardiac myocytes
(cardiac muscle cells) was observed. This study provides a strong support for the use of umbilical cord
blood as a treatment option for patients with heart attack.

11

Arthur F. Gmitro, Ph.D

University of Arizona
Award Amount FY08: $50,000

Ultra-Miniature Endoscopes for Biomedical Imaging
The objectives of this research was to build miniature endoscopes with simultaneous white-light and
fluorescence imaging capability and to demonstrate unique applications for such an instrument. We
have built 0.5mm diameter catheters exploiting the illumination concepts of numerical aperture sharing
and crossed polarizers. Such techniques provide excellent rejection of unwanted signal from the input
end of the imaging catheter and enable illuminations and collection down the same fiber optic imaging
bundle. Some assembly and testing remains to be done on the multi-modal aspects of the system
(white-light and fluorescence). Submillimeter catheters were built with conventional separate illumination
and imaging channels for imaging mouse models of Barrett’s esophagus. Such endoscopes can image
in vivo mouse esophagus with little trauma to the animal as well as detect color and large textural
variations. Further testing of the ultra-miniature multi-modal endoscope will be conducted with this
animal model.
Kano AL, Gmitro AF. Ultrathin Fiberscope Utilizing a Single Channel for Both Illumination and
Imaging. OSA Frontiers in Optics 2005. FTuG4. Tucson, AZ. 2005.
Kano, AL, Koshel RJ, Gmitro AF. Broadband Endoscopic Imaging Through a Single Fiberoptic
Channel. SPIE Optics and Photonics. 6668-7. San Diego, CA. 2007.

12

Leslie Gunatilaka, Ph.D.

University of Arizona
Award Amount FY08: $150,000

Discovery and Development of Novel Inhibitors of Cell Motility from Desert Organisms
The overall goal of this inter-institutional multidisciplinary project is to investigate Sonoran desert
organisms for novel cell motility (migration) inhibitors, and to conduct structure-activity relationship
(SAR) studies of beauvericin, a fungal metabolite encountered in a previously funded ABRC project.
During the course of the third year of this project, mutasynthesis was used to produce analogs of
beauvericin. It was demonstrated that a KIVR knockout B. bassiana strain can be used for the efficient
mutasynthesis of unnatural beauvericin congeners. Simultaneous feeding of precursor analogs enabled
the combinatorial mutasynthesis of scrambled beauvericins, some assembled entirely from unnatural
precursors. The effects of the introduced structural changes on the antiproliferative and cell migration
inhibitory activities of these analogs were also evaluated. To expedite production of additional analogs
of beauvericin, the gene encoding the BbBEAS nonribosomal peptide synthetase was isolated from
B. bassiana and confirmed to be responsible for beauvericin biosynthesis by targeted disruption.
Heterologous expression of the bbBeas gene in E. coli to produce the BbBEAS enzyme provided a strain
proficient in beauvericin biosynthesis which could be exploited for the production of further analogs
of beauvericin. We are hopeful that non-cytotoxic compounds with cell migration inhibitory activity
will provide lead compounds that can be developed into natural product-based drugs that can be used
to treat metastatic solid tumors.
Xu Y, Orozco R, Wijeratne K, Gunatilaka L, Stock P, Molnar I. Biosynthesis of the Cyclooligomer
Depsipeptide Beauvericin, a Virulence Factor of the Entomopathogenic Fungus Beauveria bassiana.
Chemistry and Biology. 15: 898-907. 2008.
Xu Y, Wijeratne K, Espinosa-Artiles P, Gunatilaka L, Molnar I. Combinatorial Mutasynthesis of
Scrambled Beauvericins, Cyclooligomer Depsipeptide Cell Migration Inhibitors from Beauveria bassiana.
ChemBioChem. 2008. In press.

13

Laurence H. Hurley, Ph.D.

University of Arizona
Award Amount FY08: $50,000

Structure and Functional Role of GGA Repeats in c-myb Promoter Activity in Leukemia
The overall goal of this proposal is to study the structure and function of GGA repeats in the c-myb
promoter and identify small molecules that selectively bind to the c-myb promoter and prevent
transcription.
During the time period covered by this report, we have made progress on specific aims 1 and 2. These
specific aims are 1) to identify the cis elements within the GGA repeat region required for c-myb
promoter activity, and 2) to identify transcription factors that bind to the GGA repeat region.
In addressing specific aim 1, we have employed a differentiation system of leukemia cells to investigate
the role of the c-myb G-quadruplexes in regulation of the endogenous (originating from within the
organism) c-myb promoter, and our data verify that the c-myb G-quadruplexes are involved in
downregulation of c-myb expression in the cells. In addressing specific aim 2, we have investigated the
role of endogenous MAZ in c-myb transcription and demonstrated that the levels of MAZ are inversely
related with those of c-myb transcription, implicating that the role of endogenous MAZ is downregulation
of c-myb transcription.
Palumbo SL, Memmott RM, Uribe DJ, Krotova-Kahn Y, Hurley LH, Ebbinghaus SW. A Novel Gquadruplex-forming GGA Repeat Region in the c-myb Promoter Is a Critical Regulator of Promoter
Activity. Nucleic Acids Res. 36:1755-69. 2008.

14

Laurence H. Hurley, Ph.D.

University of Arizona
Award Amount FY 2008: $166,269

Drug Targeting the i-Motif in the c-MYC Promoter
The overall objective of this proposal is to characterize the structure of the i-motif in the silencer
element of the c-MYC promoter and also its drug complexes, which will then be used as a basis for
drug design and development. The long-term objective is to identify a small molecule that will selectively
modulate c-MYC gene expression and then work to identify a clinical candidate molecule.
During the time period covered by this report, we have made progress on specific aims 1–3. These
specific aims are 1) to define the structure of the biologically relevant i-motif in the promoter region
of c-MYC and its drug complexes by NMR, 2) to define the structure of the biologically relevant
i-motif in the promoter region of c-MYC and its drug complexes by calorimetry, and 3) to define the
overall structure of the silencer element in the c-MYC promoter and its complexes with agents that
modulate c-MYC gene expression.
In the last 12 months we have transferred our efforts to the Bcl-2 promoter but the specific aims have
remained the same. The reason for this change is two-fold. First, the i-motif-interactive compounds
identified for Bcl-2 are more potent and specific for Bcl-2 than c-MYC. Second, our G-quadruplex
drug discovery effort for c-MYC has progressed to a point where prioritizing c-MYC as a drug target
fell lower than Bcl-2. Thus, what we had learned from the c-MYC i-motif project was quickly applied
to
the
Bcl-2 with the results outlined in the report. We are now close to having a viable proposal for a drug
discovery program using the i-motif as a target for Bcl-2. We could not have done this without the
two years prior experience with the i-motif in c-MYC.

15

Edwin A. Lewis, Ph.D.

Northern Arizona University
Award Amount FY 2008: $149,920

Deconvoluting the Structural Heterogeneity of the Bcl-2 Promoter Quadruplex
to Enhance Drug Targeting
Bcl-2 protein functions as an inhibitor of cell death. Approximately one third of all cancers involve
Bcl-2 over expression. Studies of anti-Bcl-2 agents have demonstrated improved antitumor activity.
The objective of this research was to characterize non-helical structures formed in the regulatory region
of the Bcl-2 gene. We have characterized the structure and stability of Bcl-2 promoter quadruplexes
using DSC, CD, AUC, and Computational methods. We have shown that the Bcl-2 promoter sequence
quadruplexes and their small drug interactions are similar to those determined previously for c-MYC.
We have shown that the WT Bcl-2 sequence forms fewer folded conformers than might be predicted
from its sequence. We found a similar result for K-ras, whose expression is a hallmark for pancreatic
cancer.
The hope is that drug recognition or binding to non-helical promoter sequence structures could be
used to turn off a number of cancer causing genes like Bcl-2, c-MYC, and K-ras.
Cashman D, Freyer MW, Dettler J, Hurley LH, Lewis EA. Molecular Modeling and Biophysical
Analysis of the c-MYC NHE-III1 Silencer Element. J of Molecular Modeling. 14: 93-101. 2008.
Dettler JM, Buscaglia R, Cashman D, Blynn M, Lewis EA. Structural Stability of a Mutant Construct
of the i-Motif Forming Sequence in the Human c-MYC NHE III1. Biophys J. 2009. Submitted.
Dettler JM, Le V, Blynn M, Lewis EA. DSC Deconvolution of the Structural Complexity of c-MYC
P1 Promoter G-Quadruplexes. Frontiers in Nucleic Acids. 60th Southeastern Regional Meeting of the
American Chemical Society. Nashville, TN. 2008.
Le V, Blynn M, Dettler JM, Lewis EA. Conformational Equilibria in Capped c-MYC P1 Promoter
Sequence G-Quadruplexes. Frontiers in Nucleic Acids. 60th Southeastern Regional Meeting of the
American Chemical Society. Nashville, TN. 2008.

16

John Lewis, M.D., MPH

Inter Tribal Council
Award Amount FY: $150,000

Promoting Tribal Community Participation in Biomedical Research
This project is designed to promote tribal participation in health research. There are 22 tribes in
Arizona, and most have not actively participated in research. The tribes are suffering from poor health
generally, and health research holds the possibility of improving health in these communities. The
project is being conducted in three phases:
1. Overview of current tribal research review processes–identifying what processes tribes are currently
doing to determine whether or not they will participate in research.
2. Tribal research agenda setting–providing assistance to tribes to set their own research agendas and
priorities.
3. Development of a Regional Tribal Institutional Review Board (IRB)–the IRB focuses on human
subjects protections as well as community protections in the research process.
Phase 1 is complete, and we are in the process of conducting phases 2 and 3 with 18 tribes that have
agreed to participate. We will finish the project by June 2009.

Rena Li, Ph.D.

Sun Health Research Institute
Award Amount FY08: $50,000

Roles of Estrogen in BACE Regulation in Vitro and in Vivo Systems
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Postmenopausal women
have a higher risk of developing AD than age-matched men, which might be related to the loss of estrogen
after menopause. We recently discovered that β-secretase (BACE1) enzymatic activity is significantly
increased in AD brains and CSF. While it is not known whether estrogen plays a role in BACE1
activity, we studied the effect of estrogen and its receptors on regulation of the BACE1 in animal
model and culture cells. Our data demonstrated that BACE1, the key enzyme for generation of beta
amyloid protein, was elevated in AD animals lacking brain estrogen. The elevation of BACE1 in the
AD mice is associated with earlier and more severe AD neuropathology observed in the brain. To
further study the effect of estrogen on BACE1 gene regulation, we transfected BACE1 promoter into
a stable cell line and examined the effect of 17α- and 17β-estradiol on the transcriptional activity of
BACE1. Our data showed a down regulation of BACE1 by estrogen in vitro. Our ultimate goal is to
identify the key mechanisms of estrogen action in AS pathogenesis and provide scientific evidence for
developing novel alternative estrogen therapies to treat and even prevent AD.

17

Lonnie P. Lybarger, Ph.D.

University of Arizona
Award Amount FY08: $50,000

CD8 Cell Printing Using Engineered MHC Class I Molecules
The goal of this research project is to evaluate the utility of a promising new vaccine technology for
the generation of anti-cancer immune responses. Cancer is a leading health concern in Arizona, with
approximately 24,000 new cases in Arizona in 2004. The immune system, through MHC class I
molecules, can detect and eliminated tumor cells. Here, we have developed a novel strategy to engineer
MHC class I molecules to be especially potent in terms of their ability to stimulate anti-cancer T-cells.
This project will compare the ability of these engineered molecules to prime anti-cancer immune
responses versus more conventional vaccine approaches in mouse models that mimic human cancers.
The preliminary data we have generated during the course of these studies strongly suggest that our
molecules are potent vaccine agents.
Lybarger L, Li G, Ordaz M, Kunke K, Andreansky S. Single-chain Trimers for Efficient Presentation
of Influenza Virus Class 1 Epitopes. Keystone Symposium: Viral Immunity. Keystone, CO. January
2008.
Ordaz M, Ramanathapuram L, Akporiaye E, Li G, Andreansky S, Lybarger L. Eliciting Anti-tumor
Responses with MHC 1 Single-chain Trimer Vaccines. Cancer Immunology and Immunotherapy:
Realizing the Promise. National Institutes of Health. Bethesda, MD. September 2008.

18

Istvan Molnar, Ph.D.

University of Arizona
Award Amount FY08: $49,623

Discovery, Optimization of Production and Initial Characterization of Novel Anticancer
Drug Lead Compounds from Bacteria Collected from the Rhizosphere of Desert Plants
The objective of the project was to discover novel natural products in a unique collection of bacteria
at the Natural Products Center, University of Arizona, for the development of anticancer drugs. During
the 3-year project, we have investigated 1,079 bacterial strains, conducted solid-state fermentations in
4 culture media with 716 strains, and assayed the resulting 3,268 extracts both in a mechanism-based
and a general cytotoxicity assay. Prioritization of positive extracts involved molecular taxonomy (523
strains total);counter-screening against normal human cells (208 extracts total); scale-up of the
fermentation process in liquid cultures (31 extracts total); and determination of apparent yield and
potency. Ten large scale extracts, produced by10 strains representing 6 bacterial species, were finally
selected for further study as future extension of the project. These extracts could contain novel cytotoxic
metabolites that might be used for anticancer chemotherapy, improving the health prognosis of cancer
patients.

19

Jitendran Muthuswamy, Ph.D.

Arizona State University
Award Amount FY08: $150,000

Microactuated Microelectrodes to Assess Cortical Roles in Memory Deficits
During FY08, progress was made in the following four critical areas: 1) we demonstrated that novel
doped polysilicon interfaces can suppress noise in electrical recording from single neurons; 2) we
assessed the tissue response to microelectrodes that move in the brain after implantation; 3) we designed,
developed and tested a novel MEMS microflex interconnect (MMFI) approach for packaging our
microchip; and 4) we demonstrated long-term recoding from cortical neurons in the brain.
The doped polysilicon interfaces significantly suppress noise in recording from single neurons in the
brain. In addition, the novel MMFI approach to packaging our implantable microdevice now enables
dramatic size and weight reduction and improvements in the reliability of the interconnect. Both of
the above strategies are novel and will find wide applications in other small-signal sensing contexts as
well as packaging of other implantable microdevices. Finally, using our novel microactuated microelectrode
arrays, we have successfully demonstrated long-term recording from single neurons in the somatosensory
cortex for periods lasting up to three weeks.
Saha R, Muthuswamy J. Structure-property Relationships in the Optimization of Polysilicon Thin
Films for Electrical Recording/Stimulation of Single Neurons. Biomedical Microdevices. 9(3): 34560. 2007.
Jackson N, Muthuswamy J. Artificial Dural Sealant that Allows Multiple Penetrations of Long-term
Implantable Brain Probes. J Neuroscience Methods. 17(1): 147-52. 2008.
Jackson N, Muthuswamy J. Flexible Chip Scale Package and Interconnect for MEMS Movable
Microelectrodes in the Brain. J Microelectromechanical Systems. 2008. Submitted.

20

Joseph Rogers, Ph.D.

Sun Health Research Institute
Award Amount FY08: $225,000

Translational Research on αβ Metabolism from Synthesis to Clearance
This multi-institutional research program seeks to discover new diagnostic and treatment methods for
Alzheimer’s disease based on synthesis and clearance of amyloid β peptide (Aβ), a molecule that forms
millions of toxic deposits in the Alzheimer’s brain. Projects 1 and 3 are collaboratively developing
methods to lower Aβ production. Project 1 has also elucidated a critical pathway for Aβ synthesis that
new drugs can target. Project 2 has shown that Alzheimer’s patients have a defect in clearing Aβ from
the body, and that this defect, which can be measured in a blood sample, may be diagnostic for
Alzheimer’s. In addition, based on the findings, Project 2 and Project 3 are collaboratively developing
methods to clear Aβ from the body at a faster rate. Arizona has some of the world’s most concentrated
Alzheimer’s populations. This project may provide new treatments and the first viable, inexpensive
diagnostic for the disorder.
Rogers J, Li R, Mastroeni D, Grover A, Leonard B, Ahern G, Cao P, Kolody H, Vedders L, Kolb WP,
Sabbagh M. Peripheral Clearance of Amylod β Peptide by Complement C3-dependent Adherence to
Erythrocytes. Neurobiology of Aging. 27(12): 1733-9. 2006.
Nie H, Li Z, Lukas RJ, Shen Y, Song L, Wang X, Yin M. Construction of SH-EP1-alpha4beta2h
APP695 Cell Line and Effects of Nicotinic Agnonists on Beta-amyloid in the Cells. Cell Mol
Neurobiology. In press.
Chirapu SR, Pachaiyappan B, Zhong Z, Abadul-Hay SO, Yuan H, Thatcher G, Shen Y, Kozikowski
AP, Petukhov PA. Molecular Modeling, Synthesis and Activity Studies of Inhibitors Targeting Alzheimer’s
Disease β-Secretase (BACE1). Biological Medicinal Chemistry Letters. In press.
Xia W, Yang T, Imeida M, Smith IM, Shen Y, Walsh DM, Selkoe DJ. A Specific ELISA for Measuring
Amyloid β-protein Oligomers in Human Plasma and the Brains of Alzheimer Patients. Archives of
Neurology. In press.
Hampel H, Shen Y, Zetterberg H, Biennow K. Biological Markers of β-Amyloid Related Mechanisms
in Alzheimer’s Disease. Lancet Neurology. In press.
Ewers M, Zhong Z, Teipel S, Buger K, Wallin A, Biennow K, Shen Y, Hampel H. Increased CSFBACE1 Activity is Associated with ApoE-ε4 Genotype in Subjects with Mild Cognitive Impairment
and Alzheimer’s Disease. Brain. 131:1252-8. 2008.

21

Zhong Z, Ewers M, Teipel S, Buger K, Wallin A, Biennow K, Hampel H, Shen Y. High Levels of BetaSecretase (BASE1) in Cerebrospinal Fluid is a Predictor of Risk in Mild Cognitive Impairment, the
Early Stage of Alzheimer’s Disease. Archive of General Psychiatry. 63(6): 718-26. 2007.
He P, Zhong A, Lindholm K, Berning L, Lee W, Lemere C, Staufenbiel M, Li R, Shen Y. Deletion of
TNF Death Receptor Inhibits Amyloid Beta Generation and Prevents Learning and Memory Deficits
in Alzheimer’s Mice. Journal of Cell Biology. 178(5): 829-41. 2007. Also appearing as Death receptor
Takes Central Stage in Nature Neuroscience. October 2007 and as a Hot Story in Science 2007.
Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, Hiltunen M, Yang SH, Zhong
Z, Shen Y, Simpkins JW, Tanzi RE. Depletion of GGA3 Stabilizes BACE and Enhances Beta-Secretase
Activity. Neuron. 54(5): 721-37. 2007.
Kim DY, Carey BW, Wang H, Ingano LA, Binshtok AM, Wertz MH, Pettintell WH, He P, Lee VM,
Woolf CJ, Kovacs DM. BACE1 Regulates Voltage-gated Sodium Channels and Neuronal Activity.
Nature Cell Biology. 9(7): 755-64. 2007.
Shen Y, He P, Zhong Z, McAllister C, Lindholm K. Distinct Destructive Signal Pathways of Neuronal
Death in Alzheimer’s Disease. Trends Molecular Medicine. 12:574-9. 2006.
Zameer A, Rangan SK, Emadi S, Nimmagadda S, Sierks MR. Anti-oligomeric Abeta Single Chain
Variable Domain Antibody Blocks Abeta Induced Toxicity Against Human Neuroblastoma Cells.
Journal Molecular Biology. In press.
Wang MS, Zameer A, Emadi S, Sierks MR. Characterizing Antibody Specificity to Different Protein
Morphologies by AFM. Langmuir. In press.
Kozikowski APA, Chen Y, Subahasish T, Zhong Z, D’Annibale MA, Shen Y, Langley BC. PKC
Activation and HDAC Inhibition-A Dual Drug Approach to Alzheimer’s Disease that Reduces Aβ
Production While Blocking Oxidative Stress. Proceedings of the National Academy of Science. In
press.
Rogers J, Li R, Mastroeni D, Brover A, Sierks MR. Anti-Aβ Antibodies Enhance C3-dependent
Adherence to Erythrocytes. Neuroscience Letters. In preparation.
Rogers J, Mastroeni D, Grover A, Coleman PD. Erythrocyte Aβ42 Levels as a Diagnostic and Biomarker
of Alzheimer’s Disease. Neurobiology of Aging. In preparation.

22

Adrienne C. Scheck, Ph.D.

St. Joseph’s Hospital
Award Amount FY08: $50,000

Molecular Analysis for the Diagnostic Identification of Clinically Aggressive Meningiomas
Meningiomas are the most commonly reported brain tumor in the US, accounting for 27% of primary
brain tumors. They are typically considered benign tumors that can be cured by complete surgical removal.
However, a percentage of patients have recurrent disease after apparently complete removal of a low
grade tumor. We have performed gene expression analysis of a large group of meningiomas to identify
genetic markers of aggressive tumors. Alterations in the expression of a number of genes involved in
the Wnt signaling pathway suggests that this pathway may be involved in meningioma progression
and/or tumor recurrence. In particular, we have found that the expression of genes encoding secreted
frizzled related proteins 1, 2 and 4 is highest in grade 1 tumors and goes down in higher grade and
recurrent tumors. Our data suggest that Wnt pathway may be a therapeutic target for the treatment
of aggressive meningiomas.
Pfisterer WK, Hendricks WP, Scheck AC, Nieman RA, Birkner TH, Krampla WW, Preul MC.
Fluorescent in situ Hybridization and ex vivo H MR Spectroscopic Examinations of Meningioma
Tumor Tissue: Is it Possible to Identify a Clinically-aggressive Subset of Benign Meningiomas?
Neurosurgery. Nov.61(5): 1048-59. 2007.
Pfisterer WK, Coons SW, Aboul-Enein A, Hendricks WP, Scheck AC, Preuhl MC. Implicating
Chromosomal Aberrations with Meningioma Growth and Recurrence; Results from FISH and MIB1 Analysis of Grades I and II Meningioma Tissue. Journal Neuro-Oncology. 87(1): 43-50.
Foureman P, Hendricks WP, Stafford P, Coons SW, Scheck AC. Gene Expression Analysis of Primary
and Recurrent Meningiomas. Society for Neuro-Oncology. Grapevine, TX. 2007
Foureman P, Fenton K, Flores K, Stafford P, Nakaji P, Scheck AC. Molecular Genetic Analysis for
Improved Prognostication of Meningiomas. Society for Neuro-Oncology. Lake Las Vegas, NV. 2008.

23

Jiaqi Shi, M.D, Ph.D.

University of Arizona
Award Amount FY08: $50,000

Deregulation of Translation Initiation by eIF3f in Melanoma
This project investigated the hypothesis that eIF3f is a negative regulator of translation and decreased
eIF3f expression contributes to melanoma tumorigenesis by deregulating translation and apoptosis. In
previous reports, we have demonstrated allelic loss of eIF3f gene in melanoma using LOH and gene
copy number analysis. Our eIF3f gene mutation analysis suggested that mutation may not be the
mechanisms of decreased eIF3f expression in melanoma. Here we further confirmed the decreased
eIF3f protein expression in melanoma using immunohistochemistry analysis. To characterize the
mechanism of eIF3f-mediated regulation of translation and apoptosis, we further investigated the
association between eIF3f and hnRNP K. We have established that hnRNP K to 28S rRNA, which
stabilized the rRNA and increased translation. These results support our hypothesis that eIF3f regulates
rRNA degradation, translation and apoptosis through interaction with hnRNP K.
Shi J, Kahle A, Hershey JW, Honchak BM, Warneke JA, Leong SP, Nelson MA. Decreased Expression
of Eukaryotic Initiation Factor 3f Deregulates Translation and Apoptosis in Tumor Cells. Oncogene.
25: 4923-36.
Doldan A, Chandramouli A, Shanas R, Barracharya A, Leong SP, Nelson MA, Shi J. Loss of the
Eukaryotic Initiation Factor 3f in Melanoma. Molecular Carcinogenesis. March 2008.
Shi J, Hershey JW, Nelson MA. Phosphorylation of the Eukaryotic Initiation Factor 3f by Cyclin
Dependent Kinase 11 During Apoptosis. FEBS Journal. 2008. Submitted.

24

Daekyu Sun, Ph.D.

University of Arizona
Award Amount FY08: $48,984

Targeting Tumor Angiogenesis Using I-motif Interactive Ligands
As a direct consequence of this work, we have made the important observation that the C-rich strand
of the double-stranded polyguanine/polycytosine (pG/pC) sequence of the VEGF promoter can
spontaneously convert to i-motif structures in a cell-free system even under physiological pH conditions.
Interestingly, we found that hnRNP K, which binds to the C-rich element in the single-stranded DNA
form, also interacts with C-rich strand of the (pG/pC) sequence of the VEGF promoters to promote
the transcription of the VEGF gene both in vitro and in vivo. However, hnRNP K binding to the Crich strand could inhibit conversion of the single-stranded DNA to i-motif structures. On the basis
of our accumulated data, we propose that an entirely new approach to anticancer drug design and
development could be evolved through the drug targeting of these secondary DNA structures.
Sun D, Guo K, Rusche J, Hurley L. Characterization of the i-motif Structures Formed by the C-rich
Strand of the Proximal Promoter Region of the Vascular Endothelial Growth Factor Gene. 98th AACR
Annual Meeting. April 2007. Los Angeles, CA.
Guo K, Gokhale V, Hurley L. Intramolecularly Folded G-quadruplex and i-motif Structures in the
Proximal Promoter of the Vascular Endothelial Growth Factor Gene. Nucleic Acids Res. 36(14): 45984608. August 2008.

Tom Tsang, Ph.D.

University of Arizona
Award Amount FY08: $50,000
Cancer Immunotherapy by TCR-Modified HSC Transfer

More than 10,000 people die of cancer each year in Arizona. Improved treatments are urgently needed.
Our project aims to combine gene therapy, immunotherapy, and non-embroyonic stem cell therapy
into a novel anti-cancer strategy. New genes that can recognize and destroy cancer cells will be created
and introduced into non-embryonic stem cells to create a new cancer-fighting, designer immune
system. We have successfully constructed a new cancer fighting gene construct and inserted it into a
replication-defective lentiviral (HIV) virus. We are now evaluating the transfer of this construct into
non-embryonic stem cells and its expression in mature immune cells. We will then test the ability of
animals with the anti-cancer, designer immune systems to reject cancer cells.

25

Jie Wu, M.D., Ph.D.

St. Joseph’s Hospital
Award Amount FY08: $48,885

Nicotine Acetylcholine Receptors in the VTA and Nicotine Dependence
Nicotine acetylcholine receptors (nAChRs) expressed in the brain reward center (ventral tegmental area,
VTA) contain devise subunit compositions and contribute generally to pleasure, reward, and drug
reinforcement. Under ABRC support, we have clarified three functional subtypes (ID, IID, and IIID)
of nAChRs, which are combined with different subunits. We further found that three nAChR subtypes
activation and desensitization are different to smoking relevant-concentrations of nicotine, suggesting
they play different roles in nicotine reward and dependence. More interestingly, chronic exposure to
nicotine (mimic smoking process) selectively up-regulated ID but down-regulated IID nAChRs, further
suggesting that ID type of nAChR likely plays critical roles in nicotine reward and dependence. The
finding of “the switch of nAChR subunits” during chronic nicotine exposure provides not only the
new insights into an improved understanding of nicotine reward and dependence, but also opens a
new window to develop novel drugs for smoking cessation in Arizona.

26

Section B
Continuing Contracts
Medical Research
Year Two
FY 2008

27

28

Craig A. Aspinwall, Ph.D.

University of Arizona
Award Amount FY08: $48,323

Stabalized Polymer Phospholoid Imaging Probes
For project year 2 we have further developed the proposed nanometer-sized, biomimetic chemical
labels, further expanding the utility, range of applications and performance of these novel imaging agents.
Our primary efforts have focused on developing second generation fluorescent cores that are brighter,
less environmentally sensitive and contain a broader range of dye molecules, enabling higher degrees
of multiplexing. Additionally, we have investigated a second generation coating process which allows
the utilization of commerically available, more chemically benign phospholipids. Physical and chemical
characterization of the probes has been performed and functional characterization in model systems
was begun. When fully developed, these probes will provide a novel class of imaging agents for disease
diagnosis, prognosis and early detection of disease states.

Kobus Barnard, Ph.D.

University of Arizona
Award Amount FY08: $50,000
Genetics Diagnostics of Angiogenesis

The overall goal of this project is to identify genes that, when on or off are 1) indicators of small blood
vessel (microvessel) health, and 2) potential targets for new therapies. Work in the previous funding
period showed that microvessels can exist in three distinct health conditions. Recent work has focused
on characterizing and exploiting the highly dynamic gene expression profiles associated with these
conditions. For example, by examining gene expression profiles of implanted tissue, we have found
that fully 60% of the genes were upregulated in the second week, relative to the first, pointing to great
potential for determining reliable assay to diagnose microvessel health. To understand the reliability
of such assays, we have also pursued a new approach for evaluating microarray data analysis methods
that is based on phenotypic classification performance as this directly links to what is needed to
characterize diagnostic tools.

29

Yongchang Chang, M.D., Ph.D.

St. Joseph’s Hospital
Award Amount FY08: $49,973

Mechanisms of ρ1 GABAC Receptor Activation and Antagonism
With the support of ABRC last year, we have studied additional regions around the GABA binding
pockets and accumulated more data for future publication. With enough preliminary data, we have
submitted an NIH R01 grant proposal. We also performed additional experiments for the previous
two manuscripts to address peer-reviewers’ comments and have recently published one paper entitled
“Structural determinants for antagonist pharmacology that distinguish the ρ1 GABAC receptor from
GABAA receptors” in Moleuclar Pharmacology. We have submitted another manuscript entitled “Agonistand antagonist-induced conformational changes of loop F and their contributions to the ρ1 GABA
receptor function” to Journal of Physiology. These studies helped us to better understand the structural
basis for GABA receptor function. They will help us in the future to design new GABA receptor
subtype specific compounds to treat neurological and psychiatric disorders such as sleep disorders,
seizures, depression, and schizophrenia, which affect many Arizonans.
Zhang J, Xue F, Chang Y. Structural Determinants for Antagonist Pharmacology that Distinguish the
ρ1 GABAc receptor from GABAa Receptors. Molecular Pharmacology. 74(4):1-11. 2008.
Zhang, Xue F, Chang Y. Agonist- and Antagonist Induced Conformational Changes of Loop F and
Their Contributions to the ρ1 GABA Receptor Function. 2008. Submitted to Journal of Physiology.

30

J. Richard Coast, Ph.D.

Northern Arizona University
Award Amount FY08 : $43,130

Fatigue and Training of Respiratory Muscles via Non-Respiratory Activity: Implications
for Rehabilitation
This project was designed to evaluate whether core exercises could fatigue the respiratory muscles and
whether those activities could be used to train the respiratory muscles. Initially, we performed studies
that showed non-respiratory exercises (sit-ups) caused fatigue of the respiratory muscles, and that other
easier, non-respiratory exercises such as toe-touches activated the respiratory muscles. In the second
year, we used those exercises to train the respiratory muscles. The first study used sit-up training over
12 weeks to show that both inspiratory and expiratory muscle strength increased. Along with these
increases, we saw increases in diaphragm thickness as measured by ultrasound, which indicated an
increase in muscle mass in response to the training. This study also showed that respiratory muscle
endurance was increased. The second study used some of the easier core exercises (e.g. toe-touches,
trunk twists) to determine whether that type of exercise would also increase respiratory muscle strength.
While the results were not as clear cut as those of the sit-up training study, they did result in increases
in both inspiratory and expiratory muscle strength. This work, particularly the second training study,
argue that in people suffering from respiratory muscle weakness (e.g. pulmonary patients), nonrespiratory training may result in improvements in respiratory muscles strength and/or endurance. If
proven to work, this may provide a useful adjunct therapy to pulmonary rehabilitation. We are currently
trying to find clinical collaborators for future studies in pulmonary patients.

Paul Coleman, Ph.D.

Sun Health Research Institute
Award Amount FY08: $50,000

Development and Validation of a Blood Diagnostic for Alzheimer’s Disease
We now know that Alzheimer’s disease starts decades before it is clinically diagnosed, so that the disease
has decades to damage the brain before the effects of disease become severe enough to come to medical
attention. The fact that Alzheimer’s disease starts decades before it is diagnosed using current methods
argues for a better method of diagnosis. We have evidence that a blood test may provide this better
method. Our first goal is to determine whether we can use a blood test to distinguish people already
diagnosed with Alzheimer’s disease. To that end we have collected blood samples from almost 200 people,
half with Alzheimer’s disease, the other half without Alzheimer’s disease. Our collection of sample
material is almost complete at which time we will analyze our data to determine how well our blood
test works.

31

John K. DiBaise, M.D.

Mayo Clinic Scottsdale
Award Amount FY08: $136,322

Tranmucosal Delivery of Erythromycin to Treat Gastroparesis
Gastroparesis, a condition in which an abnormal delay in stomach emptying occurs, is commonly
associated with diabetes mellitus and results in numerous gastrointestinal (GI) symptoms and inconsistent
delivery of medications. This is an important problem for Arizona because of the high incidence of
diabetes, particularly among the Native American population. A method to deliver medications that
improve stomach emptying that bypasses the GI tract may provide more consistent levels of these
drugs and result in improvement in gastroparetic symptoms and diabetes control. The goal of this research
study is to develop a sublingual system that is able to deliver therapeutic levels of erythromycin, a
potent stimulant of stomach emptying. During the study’s second year, we have successfully a) augmented
our in vitro release data showing erythromycin release from Carbopol across cellular monolayers, b)
displayed the pharmacokinetics and tissue sequestration of the drug in our animal models, and c)
compared this performance to human subjects. Remaining work will refine our formulation and
document its effect on gastric emptying.

Kathleen Dixon, Ph.D.

University of Arizona
Award Amount FY08: $149,822
Imaging of Markers for Skin Cancer Risk

Arizona has one of the highest rates of skin cancer in the world. Exposure to UV radiation in sunlight
is a major risk factor for skin cancer development. We have established a statewide multidisciplinary
collaboration for the image analysis of cellular responses to UV radiation. This work focuses on the
identification of skin cancer susceptibility factors and the development of chemopreventive agents. This
collaborative project involves investigators at two major Arizona universities (University of Arizona and
Northern Arizona University) including mathematicians and statisticians from UA and biomedical
scientists from NAU College of Engineering and Natural Sciences. The ultimate goal of this work is
to provide tools that can be used in a clinical setting to monitor skin cancer susceptibility, progression,
and responses to prevention/intervention strategies.

32

Shona T. Dougherty, M.B. Ch.B., Ph.D.

University of Arizona
Award Amount FY08: $49,535

Molecular Therapy of Bladder Cancer
Over 1000 cases of bladder cancer are diagnosed each year in the state of Arizona. The objective of
this study is to explore the therapeutic potential of a novel approach to the treatment of this disease
that exploits the differential production by the tumor cell population of a particular soluble molecule
known as VEGF. Specifically, through the use of various genetic engineering techniques we have
generated an artificial receptor that can bind VEGF and, upon doing so, induce cells to die. This
receptor has been introduced and expressed in bladder cells using a specially modified non-infectious
virus as a vehicle and its functional activity confirmed. Ongoing studies are concerned with further
exploring the therapeutic potential of this exciting approach. It is essential that such work be carried
out in order to ensure that the proposed treatment is both safe and effective prior to the initiation of
clinical studies.
Chaplin DJ, Dougherty GJ, Siemann D. Vascular Disrupting Agents. [Eds Davis DW, Herbest RS,
Abbruzzese JL.] Antiangiogenic Cancer Therapy. Chapter 14: 329-64. 2007.
Dougherty GJ, Dougherty ST. Exploiting the Tumor Microenvironment in the Development of
Targeted Cancer Gene Therapy. Cancer Gene Therapy. 2008. In press.
Dougherty ST. Vascular Targeted Cancer Gene Therapy: Potential and Challenges. ESH-STROMA
Consortium International Conference. Mandelieu, France. 2007.
Dougherty ST. Exploiting the Tumor Microenvironment in the Development of Targeted Cancer Gene
Therapy. The 11th International Tumor Microenvironment Workshop. Miami, FL. 2008.

33

Lars Ewell, PhD

University of Arizona
Award Amount FY08: $50,000

Diffusion Weighted MRI and Magnetic Resonance Spectroscopy to Differentiate Radiation
Necrosis and Recurrent Disease in Gliomas
We have continued to analyze the substantial amount of image data we have acquired from the imaging
protocol that was initiated in conjunction with the study this grant is supporting. The funds have allowed
us to hire additional researchers, Tim McDaniels (PhD) and Amarjeet Bhullar (PhD). They have taken
over from Naren Vijayakumar, who graduated this (fall) semester with his master’s degree in
electrical/computer engineering. His thesis title was “Multimodality Image Registration Using Gradient
Information and Clustering.” In his thesis, he discussed how best to align (register) two different sets
of MRI images. This alignment is important when comparing MRI scans taken at different times, such
as when attempting to assess disease progression. The analysis of imaging data has progressed, as
indicated below.
Ewell L, Vijayakumar N, Rodriguez J, Stea B. Inferior Brain Lesion Monitored Using Diffusion
Weighted Magnetic Resonance Imaging. Sino-American Network for Tharpeutic Radiology and
Oncology. Beijing, China. 2008.
Bhullar A, Ewell L, McDaniels T, Stea B. Metabolic Concentrations and Ratios of Brain Tissue.
Frontiers in Medical Research. Tucson, AZ. 2008

34

Robert J. Gillies, Ph.D.

University of Arizona
Award Amount FY08: $250,000

Multimeric Ligands for Targeting Cancer for Imaging and Therapy
Our goal for treatment of pancreatic cancer is to develop multimeric therapeutic ligands that can target
cancer cells from normal cells in humans. A ligand is a molecule that contains more than one ligand
binding motif attached to a backbone linker, a nanoparticle. Cell surface receptors are targets since
they express highly selective binding for ligands and are accessible from outside the cell for ease of
interaction. These particles can contain copies of the same ligand or copies of different ligands allowing
cross-linking of two or more different receptors for higher specificity.
This project is important as it is focused on pancreatic adenocarcinoma, a devastating disease with high
mortality. The technology was invented at the University of Arizona and our research group remains
a leader in the discovery and design of multi ligands complexes. Two emerging strengths in Arizona
are both therapeutics and imaging for which these ligands are used.
Balagurunathan Y, Morse DL, Hostetter G, Shanmugam V, Stafford P, Shack, S, Pearson J, Trissal M,
Demeure MJ, Von Hoff DD, Hruby VJ, Gillies RJ, Han H. Gene Expression Profiling-based
Identification of Cell-surface Targets for Developing Multimeric Ligands in Pancreatic Cancer. Molecular
Cancer Therapeutics. 7(9): 3071-80. 2008.
Black KC, Kirkpatrick ND, Troutman TS, Xu L, Vagner J, Gillies RJ, Barton JK, Utzinger U,
Romanowski M. Gold Nanorods Targeted to Delta Opioid Receptor: Plasmon-resonant Contrast and
Photothermal Agents. Molecular Imaging. 7(1): 50-7. 2008.
Gao F, Handl H, Vagner J, Hruby VJ, Gillies RJ. Convenient and Efficient Synthesis of a Lanthanide3+coordinated, Diethylene Triamine Pentaacetic Acid Labeled Biopolymer as an Assay for the
Cholecystokinin B Receptor. Journal of Applied Polymer Science. 106(4). 2683-8. 2007.
Lee YS, Agnes RS, Cain JP, Kulkarni V, Cai M, Salibay CCK, Petrov R, Mayorov A, Vagner J,
Trivedi D, Davis P, Ma S, Lai J, Porreca F, Vardanyan R, Hruby VJ. Opioid and Melanocortin Receptors:
Do They Have Overlapping Pharmacophores? Biopolymers. 90:433-8. 2008.
Mayorov AV, Cai M, Palmer ES, Dedek MM, Cain JP, Van Scoy AR, Tan B, Vagner J, Trivedi D, Hruby
VJ. Structure-Activity Relationships of Cyclic Lactam Analogues of α-Melanocyte-Stimulating Hormone
(α-MSH) Targeting the Human Melanocortin-3 Receptor. Journal of Medicinal Chemistry. 51(2):18795. 2008.
Shewmake TA, Francisco JS, Gillies RJ, Caplan MR. Effects of Linker Properties on Multivalent
Targeting. Biomacromolecules. 2008. In press.

35

Stukel JM, Parks J, Caplan MR, Helms-Tillery S. Temporal and Spatial Control of Neural Effects
Following Intracerebral Microinfusion. Journal of Drug Targeting. 16 (3):198-205. 2008.
Stukel JM, Heys JJ, Caplan MR. Optimizing Delivery of Multivalent Targeting Constructs for Detection
of Secondary Tumors. Annals of Biomedical Engineering. 36 (7): 1291-304. 2008.
Vagner J, Qu H, Hruby VJ. Peptidomimetics, a Synthetic Tool of Drug Discovery. Current Opinion
in Chemical Biology. 12(3): 292-6. 2008.
Vagner J, Xu L, Handl HL, Josan JS, Morse DL, Mash EA, Gillies RJ. Hruby VJ. Heterobivalent
Ligands Crosslink Multiple Cell-surface Receptors: The Human Melanocortin-4 and δ-opioid Receptors.
Angewandte Chemie, International Edition. 47(9):1685-8. 2008.
Caplan MR, Rosca EV, Gillies RJ. Molecular Targeting via Multivalency: Tradeoff Between Specificity
and Concentration. Biomedical Engineering Society. St. Louis, MO. 2008.
Fernandes SM, Sankaranarayanan R, Xu L, Josan J, Vagner J, Gillies RJ, Hruby VJ. Synthesis of
Bivalent MSH Ligands and Evaluation of Their Binding to hMC4R Using MSH Lanthaligand. 20th
American Peptide Symposium. Montreal. 2007.
Hruby VJ, Josan J, Vagner J, Sankaranarayanan JR, Mash E, Handl H, Xu L, Gillies JR. Synthesis and
Biological Properties of Multimeric Heterobivalent Complex Ligand That Can Bind to Two or More
Cell Surface Proteins for Detection and Treatment of Cancer. International Modern Solid Phase
Peptide Synthesis & Its Application Symposium. (7th Australian Peptide Symposium.) Port Douglas.
Australia. 2007.
Hruby VJ, Josan J, Sankaranarayanan R, Fernandes S, Vagner J, Jagadish B, Handl HL, Xu L, and
Gillies RJ. Design, Synthesis and Biological Evaluation of Novel Multimeric Heterovalent Ligand for
Detection of Cancer. Imaging 2020 Conference, Jackson Hole, Wyoming, September 2007.
Josan JS, Vagner J, Xu L, Morse DL, Gillies RJ, and Hruby VJ. A Novel Targeting Approach to
Molecular Imaging Based on Heteromultivalency. Contrast Media Research Symposium, Banff,
Alberta, Canada, October 2007.
Josan JS, Sankaranarayanan R, Handl HL, Fernandes S, Xu L, Vagner J, Gillies RJ, Hruby VJ.
Heterobivalent Ligands Crosslink Multiple Cell Surface Receptors. 20th American Peptide Symposium.
Montreal. 2007.
Morse DL, Balagurunathan Y, Trissal M, Shanmugam V, Stafford P, Hostetter G, Han H, Gillies RJ.
Identification of Novel Pancreatic Adenocarcinoma Cell-Surface Targets for Development of Imaging
Agents by Gene Expression Profiling and Tissue Microarray. World Molecular Imaging Congress. 2008.

36

Rosca EV, Caplan MR. Enhancement of Specific Drug Targeting via Multivalency. Biomedical
Engineering Society. Los Angeles, CA. 2007.
Rosca EV, Caplan MR. Specificity of Multivalent Is Concentration Dependent. Society For Biomaterials.
Atlanta, GA. 2008.
Shewmake TA, Solis FJ, Gillies JR, Caplan MR. Effects of Linker Properties on Multivalent Targeting
of Drugs or Imaging Contrast Agents. Biomedical Engineering Society. St. Louis, MO. 2008.
Stukel M, Caplan MR. Economical Synthesis and Evaluation of Cancer Targeting Constructs. Society
for Biomaterials. Atlanta, GA. 2008.
Stukel JM, Caplan MR. Optimizing Delivery of Multivalent Targeting Constructs. Biomedical
Engineering Society. Los Angeles, CA. 2007.

John G. Hildebrand, Ph.D.

University of Arizona
Award Amount FY08: $49,999

Kissing Bugs in Southern Arizona Potential Risks for Human Health and Development of Tools
for Monitoring and Control
We continued our studies on the species distribution of kissing bugs in the vicinity of Tucson. The
most abundant species continue to be Triatoma rubida. We launched an extensive collection campaign
with public participation that has yielded about 800 bugs since March 2008, all of which will be
individually analyzed for the presence of the parasite Trypanosoma cruzi, the causative agent of Chagas’
Disease. This parasite is transmitted through the insects’ feces. We are finalizing a comprehensive study
that demonstrates that only adult-female T. Rubida could be efficient transmitters of the parasite. We
have successfully accomplished one of the main goals in the grant, which is to increase public awareness
for the risks attributable to these insects. During the last year of the project we will devote our efforts
to testing a protoytpic trap in the field that could divert kissing bugs from entering human houses and
thus contribute to reducing the incidence of human contacts with them in southern Arizona and the
allergic reactions that often result from their bites.

37

Richard D. Lane, M.D., Ph.D.

University of Arizona
Award Amount FY08: $150,000

Neural Basis of Vagal Tone Dysregulation in Depression
Depression is a major public health problem in Arizona. Major depressive disorder (MDD) is a common
and disabling condition for which treatment exists; however, many patients do not respond and most
do not recover fully. The purpose of the research is to examine how patterns of brain activity interact
with physiological responses (particularly heart rate variability [HRV]) in patients with MDD as
compared to healthy volunteers. If HRV is an indicator of brain activity, clinicians could use HRV to
help diagnose and treat depression, which would ultimately lead to reduction in the prevalence of
depression in Arizona.
Nine depressed patients and five controls have given consent thus far (four subjects with MDD and
two controls have completed the protocol, and one depressed subject is currently active). Thirty-two
fMRI imaging sessions have been completed, and HRV and clinical data has been collected at all
patient visits. Analysis of imaging, HRV and clinical data is being conducted as the information is
obtained.

38

Ana Maria Lopez, M.D.

University of Arizona
Award Amount FY08: $150,000

Expedited Breast Cancer: A New Model in Breast Health
Patients requiring breast biopsy were approached sequentially for participation at a community hospital
and a mammography center. Following biopsy, tissue underwent ultra-rapid processing. Slides were
reviewed by telepathology. Time assessments were collected. For the first year of the study, patients
from the mammography center received their results as per usual care and patients from the surgical
clinic received their results via video conference by a teleoncologist and also completed a satisfaction
survey. The second year of the study, recruitment continued only at the mammography center. During
this second year, patients had the option to receive results per usual care or via video- or teleconference
by a teleoncologist. 100% of patients opted to receive results via teleconference by a teleoncologist where
they also completed a satisfaction survey.
Year 1: There were 153 mammography center and 38 surgical clinic participants. On average, tissue
processing and telepatholgy interpretation was completed in < 5 hour (19% (37/191) presented difficult
diagnoses and took longer (+24 hours) to diagnose). The 38 participants from the clinic reported
overall satisfaction with EBC again, indicated they would seek EBC again, and expressed relief at
receiving prompt results.
Year 2: There were 49 mammography center participants. Tissue processing and telepathology
interpretation times are currently being evaluated. The participants from the clinic reported overall
satisfaction with EBC, indicated they would seek EBC again, and expressed relief at receiving prompt
results.
This preliminary data indicate that EBC can reduce the wait for breast biopsy results for patients. EBC
may help ameliorate health care disparities in many regions of Arizona.

39

Stephen L. Macknik, Ph.D.

St. Joseph’s Hospital
Award Amount FY08: $50,000

Blood Flow Measurements During Ictal Events: Implications for Neuroprotective Therapies
One of the crippling effects of epilepsy is the progressive development of neural sclerosis. Excessive
magnitudes of local hyperperfusion or hypoperfusion caused by seizure-related vasospasms could
potentially contribute to this debilitating problem. However, it is not known if ictal blood flow dynamics
are truly abnormal; to quantify the degree of abnormality, ictal blood flow must be compared directly
to normal peak functional blood flow within the same capillaries, which has not been done. If seizures
do cause either hypoperfusion, hyperperfusion, or both, we expect their long-term cumulative degenerative
effects to be similar to those caused by iterative mini-strokes. In such cases, therapies already developed
to protect stroke victims from ischemic cell death may also provide neuroprotection for epileptics.
Our hypothesis is that seizures cause neural damage through abnormal blood flow. The significance
of the project is that it will provide the basis to develop neuroprotective treatments from vasospasms
in epilepsy.

Lawrence J. Manderino, Ph.D.

Arizona State University
Award Amount FY08: $150,000

Metabolic Syndrome and Inflammation
Insulin resistance is reduced response to tissues to insulin. Insulin resistance in muscle can result in
type 2 diabetes mellitus, a public health concern. Recent experiments suggest that chronic inflammation
may be responsible for insulin resistance, and thus type 2 diabetes. However, it is not known what
causes the inflammation. We hypothesize that, because insulin resistance is often found in obesity, an
oversupply of fat leads to inflammation and insulin resistance. The oversupply of fat acts as an “insult”
to tissue such as muscle, producing inflammation. We want to see if fat oversupply precedes muscle
inflammation. A marker of inflammation in muscle is lkB, a protein involved in inflammation. Our
studies show that obese individuals have lower lkB protein than lean individuals, indicating muscle
inflammation. After completing these preliminary studies, we currently are completing the in vivo
portion of the clinical research (fat infusions).

40

Jesse D. Martinez, Ph.D.

University of Arizona
Award Amount FY08: $49,999

Nutritional Modulation of Colorectal Cancer Risks
Bile acids have been implicated as gastrointestinal factors that can modify risk for developing colon
cancer. Here we examine the molecular mechanism by which bile acids act at the molecular level in
order to gain insight into how they function in modifying colon cancer risk. We found that the tumor
promoting bile acid, deoxycholic acid (DCS), can modify the composition of the cell’s membrane and
that this results in simulation of growth signaling pathways. In contrast we found that a bile acid which
was shown to suppress tumor development also suppresses growth signaling pathways by also acting
at the cell’s membrane. To date our results confirm that bile acids act at the membrane, but that the
effect that they have on the membrane determines their effect on tumor development. This has
important implications for colon cancer chemoprevention because it suggests that manipulating the
composition of the plasma membrane may be a useful strategy for the prevention of colon cancer.

41

Raymond B. Nagle, M.D., Ph.D.

University of Arizona
Award Amount FY08: $50,000

Translational Regulation of Protein Expression in Prostate Cancer Progression
Mortality from prostate cancer is primarily due to metastasis to distant sites. Each year in Arizona
approximately 4300 new cases of prostate cancer are diagnosed and 500 men die due to prostate cancer.
Therefore, understanding the molecular mechanisms of prostate cancer metastasis could provide great
therapeutic potential. Laminin-332 provides stable adhesion structures in normal prostate and prevents
cellular invasion and metastasis. Its expression is lost in prostate cancer progression, and we have been
working on determining the cause of this loss. We have previously demonstrated that LM-332 loss in
prostate cancer is not due to alterations in translational regulation, nor transcriptional regulation. This
finding has led us to investigate other possible mechanisms of LM-332 loss, such as targeted protein
degradation. We have shown evidence for this mechanism of loss in this current report.
Cohen JD, Tham K, Gard JMC, Nagle RB, Monks TJ, Lau SS. C-RAF Regulates Cyclin D1 Protein
Expression Through MAPK Crosstalk with 4EBP1. Mountain West Society of Toxicology. Salt Lake
City, UT. 2008.
Gard JMC, Averill J, Vanpatten KA, Pertano G, Nagle RB. Investigation Into the Role of the PI3Kinase Pathway in Translational Repression in Prostate Carcinoma. Keystone Symposia PI3-Kinase
Signaling Pathways in Disease. Keystone, CO. 2007.
Kremer CL, Klein RR, Mendelson J, Browne W, Samadzedeh LK, Vanpatten K, Highstrom L, Pestano
GA, Nagle RB. Expression of mTOR Signaling Pathway Markers in Prostate Cancer Progression.
Prostate. 66:1203-12. 2006.

42

Alyssa Panitch, Ph.D.

St. Joseph’s Hospital
Award Amount FY08: $250,000
Biomimetic Scaffolds for Spinal Cord Regeneration

A therapeutic approach that combines the mechanical support of scaffolding with molecules that are
present during development and molecular cues to the regeneration axons, will improve the potential
for functional recovery after spinal cord injury. The hypothesis of this investigation is that complementing
biologically relevant developmental scaffolds with cell signaling peptides will improve neurite outgrowth
from primary cortical neurons and improve rate and number of regeneration neurons after spinal cord
injury. Progress over the past year has demonstrated that insertion of hyaluronic acid gels of appropriate
concentration into the injured spinal cord decrease the volume of injured tissue and improves functional
recovery. In vitro, coupling the gels with regeneration signals improves neurite extension and is anticipated
to further increase functional recovery after spinal cord injury in our in vivo model.

Mark C. Preul, M.D.

St. Joseph’s Hospital
Award Amount FY08: $150,000

A Novel Peptide Mimetic for the Immunotherapy of Brain Tumors
Direct activation of phagocytic cells therefore the final effectors of the immune response against tumors,
is a promising approach to cancer treatment. Ednogenous human serum macrophage activating factor
(MAF) which produces phagocytic activation, is efficacious against certain tumors. However, MAF
has not been studied extensively because its source, human blood, precludes its widespread experimental
use. Furthermore, MAF has not been assessed in the setting of brain cancers. We have recently developed
a novel synthetic peptide mimetic of MAF, L4MAF, which can activate microglia, the cells responsible
for the cellular immune response in the brain, in vitro. L4MAF can be mass produced and is comparatively
protected against enzymatic degradation in the bloodstream. In this project, we attempt to establish
the efficacy of L4MAF at reducing tumor growth in animal models of brain cancer.
Our previous findings reported in 2007 continue. In addition, Cytokine assays are confirming the effect
of the L4MAF radiation sensitization for tumor destruction. These promising results are anticipated
to lead to further animal studies and future clinical trials.

43

Naomi E. Rance, M.D., Ph.D.

University of Arizona
Award Amount FY08: $49,504

Effects of Estrogen Withdrawal on Hypothalamic Thermoregulation
Our goal is to provide basic information on how estrogen affects the regulation of body temperature
and thus provide insights into the cause of menopausal flushes. In the past year, we examined the
effects of estrogen and changes in environmental temperature on the activity of neurons in the
hypothalamus, the area of the brain that controls body temperature. We found that the activity of cells
in the median preoptic nucleus (MnPO) of the hypothalamus was increased in rats exposed to warm
temperatures, providing evidence that this area controls heat loss from the body. Furthermore, the
activity of MnPO neurons was reduced by estrogen replacement. These data implicate MnPO neurons
as a site of integration between the reproductive and the thermoregulation control centers in the brain.
Thus, this site could be involved in the generation of menopausal flushes.

Seth Rose, Ph.D.

Arizona State University
Award Amount FY08: $50,000

Sulfonium-Salt Suicide Inhibition (SSSi) of Cancer Cell Division
Cancer cells grow and spread because they have overcome normal cellular processes that cause abnormal
cells to self-destruct. Drugs that restore the normal behavior suffer from cancer cells becoming resistant
to them by expelling the drugs from the cell. To combat this, we devised, made, and tested thirteen
new compounds, as well as five previously prepared ones, against cancer cells. The compounds were
designed to chemically bind to their target in a novel way so they would interfere with cancer cell growth
without being subject to the effects of expulsion of the drug. We treated an enzyme with some of these
compounds and found proof of concept of the strategy. We examined how some of these compounds
may chemically achieve their cell-killing effects and used computer methods to evaluate a possible
additional, cellular target enzyme. These studies further the development of anticancer drugs for the
benefit of Arizona cancer patients.
Rose SD, Hartman RF, Han H, Zhao Y. Overcoming Drug Resistance in Cancer Cells. Medicinal
Chemistry Symposium. Northwest and Rocky Mountain Regional Meeting, American Chemical
Society. Park City, UT. 2008.

44

Samuel Schluter, Ph.D.

University of Arizona
Award Amount FY08: $150,000

Modulation of Autoimmune Disease by Natural Autoantibodies and Immunopeptides
Our focus is on natural autoantibodies that bind to the T-cell Receptor (TCR) present on T-cells, the
central players in the immune system cells. We hypothesize that such antibodies may act to suppress
pathogenic autoimmune reactions. We derived a natural anti-TCR auto monoclonal antibody (mAAb)
using B cells from an arthritis (RA) patient. This mAAb can induce the secretion of low levels of IL10 in vitro. However, in the presence of specific antigen, the mAAb induces very large amounts of IL10. This is very significant since IL-10 is one of the main cytokines used by the immune system to
inhibit and suppress immune responses. In particular, T-regulatory cells, a chief cell involved in
suppressing autoimmune reactions, secrete IL-10. The results are extremely encouraging supporting
our proposal that anti-TCR mAAbs could, in the future, be used to treat autoimmune diseases such
as RA by inducing specific T-regulatory cells.
Adelman MK, Schluter SF, Robey IF, Marchalonis JJ. Natural and Autoantibodies to Human T-cell
Receptor Vbeta Segments: Potential Roles in Immunomodulation. Crit Rev Immunol. 27(30): 22132. 2007.
Ranganathan P, Adelman MK, Schluter SF. Attempted Immunocorrection by Autoantibodies in
Inflammatory Autoimmune Disease. Immunotherapy 2008: Implementing Combinations. Havana,
Cuba. 2008.

Philip M. Service, Ph.D.

Northern Arizona University
Award Amount FY08: $47,535

Genetics of Aging: Fine-Scale Mapping of Life Span Genes in Drosophila
During this year, we made progress in two areas. First, we successfully completed screening genetic markers
that we need in order to map genes that influence life span in our fly populations. In all, we have
screened more than 370 candidate markers and have obtained 34 - 38 informative markers for each of
our three mapping crosses. During the past year we genotyped almost 1,700 individual flies for each
marker. This data will be analyzed in the coming year. Second, we substantially completed a large-scale
simulation study. These simulations are necessary to determine the best strategy for analysis of our
actual data. As a result of these simulations, we have developed a strategy that will improve our power
to detect life span genes while at the same time reducing the likelihood that we will “identify” nonexistent genes. This strategy for analysis of genetic data and gene discovery should be broadly applicable.

45

Edward B. Skibo, Ph.D.

Arizona State University
Award Amount FY08: $50,000
Non-Nucleotide Inhibitors of IMP Dehydrogenase

The cancer cell must synthesize cofactors and DNA components at a rapid pace in order to spread
through out the host. The enzyme IMP dehydrogenase (type II) plays a key role in this regard and is
often present at elevated concentrations in cancer cells. Many of the candidate IMP dehydrogenase
inhibitors are nucleotides that can interfere with other aspects of purine metabolism. Our strategy for
designing non-nucleotide inhibitors of IMP dehydrogenase is to design a purine ring mimic tethered
to amino acid residues that binds to type II enzyme. In the past year, we accomplished the following:
• Synthesis of active analogues based on QSAR studies carried out last year
• Work on isolation of recombinant human Type II IMP dehydrogenase
• Investigation of new purine mimics.
Hargreaves RHJ, David CL, Whitesell LJ, LaBarbera DV, Jamil A, Chapuis JC, Skibo EB. Discovery
of Quinolinediones Exhibiting a Heat Shock Response and Angiogenesis Inhibition. Journal of Medical
Chemistry. 51(8): 2492-501. 2008.
Hoany H, Huang X, Skibo EB. Synthesis and in vitro Evaluation of Imidazole-based Wakayin Analogues.
Organic and Biomolecular Chemistry. 6(17): 3059-64. 2008.

Lucy J. Treiman, Ph.D.

St. Joseph’s Hospital
Award Amount FY08: $50,000

How Do Febrile Seizures Cause Epilepsy: Possible Role of Gene Expression
Febrile seizures in neurologically normal young children appear to be an important risk factor for
developing epilepsy later in development. In an animal model of febrile seizures, infant rat pups exposed
to hyperthermia-induced seizures have been reported to have a lowered threshold to experimental
seizures as adults. The mechanisms of this increased neuronal excitability are not understood. Differences
in neuronal gene expression in specific areas of the brain after hyperthermia-induced seizures will be
compared with control rats 48 hours after seizures and in adult rats. The hypothesis of this project is
that acute and/or long-term changes in gene expression after hyperthermia-induced seizures compared
with control rats may help explain the increased neuronal excitability and lowered seizure threshold
seen in adult rats exposed to hyperthermia-induced seizures as pups. Identification of differences in
gene expression may lead to the development of neuroprotective interventions for children with febrile
seizures to prevent the subsequent development of chronic epilepsy.

46

Tsu-Shuen Tsao, Ph.D.

University of Arizona
Award Amount FY08: $49,999

Biological Function and Chemistry of Adiponectin Oligomerization
The overall objective of this project is to understand the role of impaired adiponectin oligomerization
in the pathogenesis of Type 2 diabetes mellitus, a major and rapidly increasing health threat in Arizona.
The data generated during the course of completing the goals set forth in Aim 1 have allowed us to
successfully apply for a research grant from the American Diabetes Association. This grant will bring
to Arizona a total of $414,000 over a period of three years from a nationally recognized foundation.
This represents a 176% return on ABRC’s investment in the form of this contract. We continue to
make significant progress in further characterizing the oligomerization mechanisms of adiponectin as
part of Aim 2. We have also confirmed our initial observation that adiponectin oligomers can interconvert
outside of circulating blood as part of Aim 3. These results will allow us to compete for additional
funding from national sources.
Thompson ACS, Davidson R, Nunez M, Tsao TS. Enhanced Adiponectin Production in Larger 3T3L1 Adipocytes Suggests Altered Regulation of Adipocyte Size in Obesity. Keystone Symposia in
Pathogenesis of Diabetes and Obesity. Keystone, CO. 2008.
Choi JE, Gorman G, Gilbert D, Tsao TS, McDonagh P. Adiponectin Treatment Attenuates Myocardial
Infarction in Zucker Diabetic Fatty Rats and Is Associated with Reduced Neutrophil Accumulation.
American Diabetes Association 68th Scientific Sessions. San Francisco, CA. 2008.
Briggs DB, Mashalidis EH, Tsao TS. Distinct Assembly Pathways for Adiponectin Oligomers Suggests
Improper Intra-Trimer Disulfide Formation as Cause of Decreased HMW Adiponectin in Insulin
Resistance. American Diabetes Association 68th Scientific Sessions. San Francisco, CA. 2008.

47

Marlys H. Witte, M.D.

University of Arizona
Award Amount FY08: $49,676
Massage Therapy in Childhood Lymphedema

Swollen or unequal limbs of children are most commonly due to birth defects of lymphatic drainage
(“congenital lymphedema [LE]”) or complications of cancer treatment (“acquired LE”), which slows
down removal of excess tissue fluid (lymph). These children often suffer severe physical and psychological
disabilities. At least several hundred Arizona children, occasionally with other family members, suffer
from childhood LE (CLE). We are testing simplified CLE management, namely a specialized massage
therapy (manual lymph drainage-MLD) without compressive bandaging in growing children to
determine responsiveness to a short and maintenance MLD regimen, compliance, and long-term
outcomes. During the second year, we trained personnel, individualized protocols, screened and enrolled
subjects ranging from toddler to adolescents with congenital and acquired LE of arms, legs and face.
Promising preliminary results showed substantial volume reduction in the swollen limbs during the
short intensive MLD monotherapy, which is being followed during home maintenance. To accrue
more subjects, we are networking with Arizona and national pediatric and cancer centers, physicians
and therapist, CLE families, and through Telemedicine links with international CLE centers of excellence
for multi-institutional collaboration.

48

George T. Wondrak, Ph.D.

University of Arizona
Award Amount FY08: $50,000

Melanoma Cell Survival Signaling by Glycolytic Intermediates
The rising incidence of skin cancers in the state of Arizona is a public health problem of increasing
concern. In the state of Arizona, melanoma accounts for only 5% of all skin cancers, but causes almost
80% of all skin cancer deaths. Metastatic melanoma is a particularly aggressive tumor that originates
from pigment producing cells in human skin. In this ABRC sponsored research period, my laboratory
has examined a novel molecular mechanism that regulates melanoma cell survival and progression. This
molecular mechanism involves reactive intermediates from cellular metabolism and their protein targets.
Based on our understanding of this mechanism, novel prototype drugs that effectively kill melanoma
cells without harming normal cells have been identified. A compound similar to reactive intermediates
from metabolism, cinnamic aldehyde derived from cinnamon, has been identified as a promising antimelanoma agent. Further research will define the role of this compound and close chemical derivatives
as potential drugs for chemoprevention and treatment of melanoma skin cancer.
Wondrak GT, Cabello CM, Villeneuve NF, Zhang S, Ley S, Sun Z, Zhang DD. Cinnamoyl-based
Nrf2-activators Targeting Human Skin Cell Photo-oxidative Stress. Free Radic Biol Med. 45(4): 38595. 2008.
Wondrak GT. Rectivity-based Drug Discovery Using Vitamin B(6)-derived Pharmacophores. Mini Rev
Med Chem. 8(5): 519-28. 2008.
Cabello CM, Bair WB3rd, Wondrak GT. Experimental Therapeutics: Targeting the Redox Achilles
Heel of Cancer. Curr Opin Investig Ddrugs. 8(12): 1022-37. 2007.
Bause SA, Lamore SD, Wondrak GT. More Than Skin Deep: The Human Skin Tissue Equivalent as
an Advanced Drug Discovery Tool. Frontiers Drug Disc Dev. 2009. In press.
Cabello CM, Wondrak GT. Targeting the NQO1-redox Achilles Heel of Cancer Using Small Molecule
Prooxidant Redox Cyclers. Proceedings of the 99th Annual Meeting of the American Association for
Cancer Research. San Diego, CA. 2007.

49

Yitshak Zohar, Ph.D.

University of Arizona
Award Amount FY08: $ 50,000

Novel Applications of Nanotechnology: Microdevices for Capture and Analysis
of Circulating Tumor Cells
The goal of this project is to use bio-technology to create microdevices for capturing specific populations
of cells from complex suspensions, such as blood, for further analysis. So far we assembled and tested
a system, incorporating fabricated microfluidic devices with bio-functional surfaces, designed to capture
cancer cells from a complex mixture. After developing the assay for functionalizing surfaces with
antibodies, we test the specific interaction between functionalized surfaces and target cells. The results
show that an anti-N-cadherin coated is highly specific in binding N-cadherin expressing prostate cancer
cells while suppressing non-specific binding of other cell types. Furthermore, although possible, the
capture of a moving cell on a functionalized surface is difficult. However, under no-flow condition,
about 5 minutes of incubation time is sufficient to capture almost all the target cells present in the
microchannel. We also obtained preliminary results regarding cell deformation and detachment due
to applied flow field.
Cheung LSL, Zheng XJ, Stopa A, Schroeder JA, Heimark RL, Baygents JC, Guzman R, Zohar Y.
Attachment and Detachment of Prostate Cancer Cells in a Microfluidic System. 12th International
Conference on Miniaturized Systems for Chemistry and Life Sciences. San Diego, CA. 2008.
Cheung LSL, Zheng XJ, Stopa A, Schroeder JA, Heimark RL, Baygents JC, Guzman R, Zohar Y.
Flow Acceleration Effect on Cancer Cell Deformation and Detachment. 22nd International Conference
on Micro Electro Mechanical Systems. Sorrento, Italy. 2009.
Guidpaty T, Cheung LSL, Jiang L, Zohar Y. Cluster Formation in Partical-laden Microchannel Flow.
First Sensor, Signal, and Information Workshop. Sedona, AZ. 2008.
Guidpaty T, Cheung LSL, Jiang L, Zohar Y. Cluster Formation and Growth in Flow of Dilute Particle
Suspension in Microchannels. 9th Annual ASME Conference on Engineering Systems Design and
Analysis. [Keynote lecture]. Haifa, Israel. 2008.

50

Section C
Continuing Contracts
Medical Research
Year One
FY 2008

51

52

Emmanule Akporiaye, Ph.D.

University of Arizona
Award Amount FY08: $50,000

Targeting TGF-β Signaling to Enhance Dendritic Cell Based Therapy of Melanoma
A major obstacle to the success of cancer immunotherapy is the diminished immune responsiveness
of patients with progressing disease. This is in part due to the suppressive effect of tumor-derived
factors such as transforming growth factor-β (TGF-β). Our goal was to block TGF-β-mediated signal
transduction to improve the effectiveness of a specialized immune cell known as dendritic cell (DC)
in treating established TGF-β-secreting malignant melanoma. We demonstrated in the test tube that
the TGF-β signaling inhibitor SM16 was able to block TGF-β-mediated signaling in DC and melanoma
tumor cells. We also successfully generated gene-modified mice with DC that are unresponsive to
TGF-β and showed that such DC are better able to initiate an immune response. Furthermore, we
tested the combination of DC plus SM16 to treat melanoma and demonstrated that although DC
vaccination was effective in suppressing tumor growth the addition of SM16 did not improve the
outcome.

53

Klaus Beyer, Ph.D.

University of Arizona
Award Amount FY08: $50,000

Membrane Interactions and Neurodegeneration in Parkinson’s Disease
This project is focused on an investigation of biomembrane associated structural transitions in the
Parkinson related protein α-synuclein. It has been shown previously that α-synuclein undergoes a coilhelix transition upon interaction with raft forming membranes. Membranes that are prone to forming
domains are prevalent in the brain and are believed to be involved in vesicular nerve transmission, a
key process that seems to be impaired in Parkinson’s disease. This causal relationship prompted us to
initiate a thorough investigation of structural properties and of the mixing dynamics of raft forming
model membranes using solid state Nuclear Magnetic Resonance (NMR) techniques. The particular
role of cholesterol on the non-ideal mixing behavior and on structural parameters such as hydrocarbon
thickness and thermal expansion coefficients in sphingomyelin containing membranes could thus be
demonstrated for the first time.
In this study we used a number of peptides selected from the primary sequence so as to represent the
structural elements of the membrane bound protein as determined earlier by NMR spectroscopy. Our
results provide strong evidence that the N-terminal protein segment, comprising residues 1-2, is crucial
for proper folding of the full length protein.
Bartels T, Lankalapalli RS, Bittman R, Beyer K, Brown MF. Raft Like Mixtures of Sphingomyelin and
Cholesterol Investigated by Solid-State 2H NMR Spectroscopy. Journal of American Chemical Society.
130: 14521-32. 2008.
Bartels T, Zhang H, Beyer K, Saavedra SS, Brown MF. Plasmon Waveguide Resonance Shows Preferential
Binding Oligomeric α-Synuclein to Raft-Like Lipid Mixtures. Biophysical Society Annual Meeting.
Boston, MA. 2009.
Bartels T, Kamp F, Nuscher B, Odoy S, Haass C, Beyer K. Lipid Interaction of α-Synuclein:
The N-Terminus Triggers Vesicle Binding and Helix Folding. The Journal of Biological Chemistry.
In press.
Bartels T, Lankalapalli RS, Bittman R, Brown MF, Beyer K. Solid-State 2H NMR Spectroscopy Reveals
Micromechanics of Raft-Like Ternary Lipid Membranes Containing Sphingomyelin and Cholesterol.
Biophysical Society Annual Meeting. Boston, MA. 2009.

54

Christopher Buneo, Ph.D.

Arizona State University
Award Amount FY08: $50,000

Contribution of Parietal Areas to State Estimation
This research is aimed at understanding how the brain combines sensory information from various
sources and uses it to guide our limb movements. Such basic sensorimotor functions can be altered by
‘strokes’ and traumatic brain injuries, as well as by the normal aging process and developmental
abnormalities. We have been studying these functions by monitoring the activity of cells in a brain
region known to be involved in sensorimotor control, the posterior parietal cortex (PPC). We have
found that in one part of the PPC cells appear to signal the position of the arm solely by using
information obtained from the muscles, i.e. they do not appear to use visual information when it is
available, suggesting visual and muscular information are integrated in another area. It is hoped that
a more complete understanding of this important function will benefit the citizens of Arizona through
improved rehabilitation protocols and assistive technologies.
Apker GA, Darling T, Bueno CA. Sensorimotor Integration During Online Movement Corrections.
Society for Neuroscience Annual Meeting. Washington, DC. 2008.
Shi Y, Bueno CA. Patterns of Directinal Errors Resulting from Endpoint Estimates of Varying Precision.
Society for Neuroscience Annual Meeting. Washington, DC. 2008.

Setsuko K. Chambers, M.D.

University of Arizona
Award Amount FY08: $50,000

Regulation of c-fms Proto Oncogene Related Breast Cancer Risk
We have shown that the HuR protein, by binding to the tail end sequences of the RNA for the c-fms
oncogene, elevates the levels of this oncogene, leading to enhanced invasiveness of breast cancer cells.
This year, we studied whether a novel binding protein we have identified, vigilin, can compete for binding
of the HuR protein to the same c-fms RNA sequences. If this competition exists, then this could be
a mechanism which could be exploited to decrease c-fms oncogene levels and turn off invasiveness and
spread of breast cancer cells. We have shown that vigilin is expressed in breast cancer cells, that it binds
to c-fms RNA both in the laboratory and in breast cancer cells, and that it binds to the same regions
of the tail end of c-fms RNA as does HuR. Most importantly, we have successfully shown that vigilin
competes for HuR binding to c-fms RNA.

55

Harinder Garewal, Ph.D.

University of Arizona
Award Amount FY08: $150,000

Hypothesis-Driven Biomarkers of Colon Cancer Risk
Arizona has 6.5 million residents. Lifetime risk of colorectal cancer is 5-6%, so 360,000 residents will
develop a colorectal cancer. Current tests to indicate need for removal of pre-cancerous growths (polyps)
or cancers in the colon are only 20-50% accurate. We have obtained 6 colon biopsies from each of
121 female and 116 male patients undergoing colonscopies at University Medical Center and evaluated
most of these biopsies for the enzyme Cytochrome c Oxidase I (CcOI). If one or more patient biopsies
has 20% or more areas in the biopsy deficient for CcOI, this corresponds fairly closely with the expected
risk for the patient, determined from polyps found, of colon cancer. Also 17 of 21 colon cancers had
deficiencies for CcOI, indicating the cancers may have arisen from a CcOI defective tissue area. These
results may allow us to devise a reliable test, performed in a physicians office, that predicts need for
removal of pre-cancerous growths.
Dvorak K, Bernstein H, Payne C, Bernstein C, Garewal H. Bile Acid Induction of Apoptosis in Relation
to Gastrointestinal Cancer. [Eds Jenkins G, Hardie L.] Bile Acids: Toxicity and Bioactivity. Chapter
3. Royal Society of Chemistry. Cambridge, UK. 2008.
Bernstein C, Bernstein H, Payne C, Dvorak K, Garewal H. Field Defects in Progression to Gastrointestinal
Tract Cancers. Cancer Letters. 260:1-10. 2008.
Bernstein H, Bernstein C, Payne C, Garewal H, Dvorak K. Adverse Effects of the Steroidal Bile Acids
in the Gastrointestinal Tract. [Ed Columbus F.] Adverse Effects of Steroids. Nova Science Publishers,
Inc. 2008.
Bernstein H, Payne C, Bernstein C, Garewal H, Dvorak K. Cancer and aging as Consequences of unRepaired DNA Damage. Cancer Research Journal. 2:2-3. 2008.

56

Leslie Gunatilaka, Ph.D.

University of Arizona
Award Among FY08: $150,000

Withaferin A Analogs Targeting Annexin II as Novel Drugs for Pancreatic Cancer
Among all cancers, pancreatic cancer has the worst survival rate and is the fourth leading cause of cancer
deaths in the United States. Unfortunately, there are no good chemotherapies available, and there is
thus an urgent need for the discovery and development of new and effective anticancer drugs to treat
pancreatic cancer. Our preliminary studies with the natural product withaferin A (WA), isolated from
the desert medicinal plant Withania somnifera (winter cherry), has led to the discovery of the protein
Annexin II as the target. With the aim of exploiting the unique potential of Annexin II as a novel
target for pancreatic cancer, we have assembled a multidisciplinary team for in vitro and in vivo
evaluation of naturally-occurring and semi-synthetic analogs of WA.
In our studies to produce WA by soil-less aeroponic cultivation of Withania somnifera, three new and
eight known analogs of WA were isolate and characterized. WA produced by this technique was used
for the semi-synthesis of seventeen of its analogs by chemical conversions and microbial biotransformations. All twenty-eight natural and semi-synthetic analogs together with WA were subjected
to anticancer bioassays involving inhibition of cancer cell proliferation/survival, heat shock induction,
disruption of cytoskeleton in normal human diploid cells, and inhibition of angiogenesis in
HUVEC-2 cells. Based on the results obtained in these assays, ten WA analogs were selected for
evaluation in progressively aggressive pancreatic cancer cell lines, BxPC-2, Miapaca-2, and Panc-1.
Outcome of these assays will be used to select promising compounds for gene expression analysis and
in vivo evaluation against pancreatic cancer.
We are hopeful that this project involving two niche areas of Arizona Biosciences Roadmap, cancer
and medically-oriented bio-agriculture, will provide appropriate candidates for further development
as mechanistically unique and clinically effective drugs to treat pancreatic cancer.

57

Melissa D. Halpern, Ph.D.

University of Arizona
Award Amount FY08: $50,000

Enterohepatic Circulation of Bile Acids in Necrotizing Enterocolitis
Necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal disease of premature infants that
affects approximately 500 premature infants in Arizona each year; 20-50% of these babies will die.
Over the last decade, the number of prematurely born infants nationwide has steadily increased and
the number of babies with NEC has also increased. Statewide, it is responsible for up to 5% of all
neonatal intensive care unit admissions and is associated with high medical costs. The exact cause of
NEC is unknown, and currently there are no specific treatments for this devastating disease. Using a
neonatal rat model of NEC, our laboratory was the first to show that elevated levels of bile acids in
the ileum (the site of NEC injury) contribute to intestinal damage during NEC. However, the
mechanisms by which bile acids accumulate and cause tissue injury have not been clarified. The goals
of this proposal are to systematically examine the mechanisms involved in bile acid induced tissue
injury during disease development using neonatal intestinal tissue cultured with inflammatory components
of the NEC intestine, including bile acids. In this year of study, we have determined that newborn
intestine reacts differently to bile acids than do intestines for older animals. The newborn intestine
appears to be less able to protect itself from potential damage from bile acids, and these data suggest
a mechanism by which premature infants may be at risk for development of this devastating disease.

Ronald P. Hammer, Jr., Ph.D.

University of Arizona
Award Amount FY08: $49,995

Brain Dopamine, Glutamate and Cortical Activity: A Rodent Model of Schizoophrenia
The broad, long-term objective of the project is to determine the brain mechanisms underlying
symptoms of schizophrenia using an experimental animal model to better define cellular and molecular
alterations. The specific aims are 1) to utilize molecular approaches to determine the nerve cells and
circuits affected by drugs that produce schizophrenia symptoms, 2) to compare the pattern of functional
activity produced by these drugs to that produced by auditory stimulation, and 3) to determine the
precise connections of the affected nerve cells. The results will allow us to better understand the final
common pathway involved in producing symptoms of schizophrenia, possibly resulting in better
therapeutic interventions targeting this pathway to help treat or cure patients with this devastating disorder.

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Paul S. Keim, Ph.D.

TGEN
Award Amount FY08: $150,000

Novel Analysis of Coccidioides Posadasii Isolates for Molecular Epidemiology
and Population Characterization of Valley Fever
The goal of this project is to develop novel genotyping techniques for Coccidioides, the cause of Valley
fever. We have made significant progress in accomplishing the stated objective. We completed the
bioinformatics analysis of all available Coccidioides genome sequences, identifying 1500 targets that
will be used in the genotyping assays. We also established a comprehensive repository of over 450
individuals strains of Coccidioides. Additionally, we developed two separate genotyping strategies, an
initial strategy to target multiple (~50) foci and a more comprehensive analysis system using all 1500
identified targets. We began development of the probes for the first system and plan to have 200
isolates typed by the first quarter of year 2. We also began design of the second system which we expect
to complete in the first quarter and move to genotyping in the second quarter. We will conduct final
analysis of data in the final quarters.

Pawel R. Kiela, Ph.D.

University of Arizona
Award Amount FY08: $50,000

Modulation of Neutroophil Function by Curcumin in Inflammatory Bowel Disease
Neutrophilis play a key role in the immune response by eliminating pathogens. However, Inflammatory
Bowel Disease (IBF), a disproportionate and persistent inflammatory process mediated by transepithelial
neutrophil migration and also a reduction of epithelial barrier function, causes perpetuation of the
inflammatory processes and tissue destruction via oxidative damage and the release of proteases. Our
central hypothesis is that curcumin affects the recruitment and function of neutrophils at multiple levels
to reduce the extent of mucosal damage in colitis. To date, we have determined that a) curcumin affects
production of epithelial cells and macrophage-derived key chemokines to reduce recruitment of
neutrophils to the site of inflammation, b) curcumin inhibits migration of neutrophils in a
chemoattractant gradient, c) curcumin inhibits neutrophil chemotaxis and chemokinesis by interfering
with signaling cascade leading to actin polymerization and formation of the leading edge, d) this is
partially due to inhibition of chemokine-induced AKT (protein kinase B) activation in neutrophils.

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Susana Martinez-Conde, Ph.D.

St. Joseph’s Hospital
Award Amount FY 2008:$ 50,000

The Effect of Progressive Supranuclear Palsy on Microsaccade Dynamics During Visual Fixation
Our eyes move continually even while we fixate our gaze on an object. If fixational eye movements are
counteracted, our visual perception of stationary objects fades completely due to neural adaptation.
When we explore a visual scene, we spend approximately 80% of the time fixating our gaze on the
various points of interest of the image. Therefore much, possibly most, of our visual experience occurs
during fixation, and fixational eye movements drive much of our perception. Thus pathological fixational
eye movements are expected to lead to vision loss, yet this has not been previously addressed in any
clinical therapy regime. We have begun to establish the contribution of fixational microsaccades in
normal and pathological vision. Our central hypothesis that microsaccades are critical to normal visual
perception during fixation, and that deficiencies in microsaccades contribute to pathological vision in
progressive supranuclear palsy (PSP). Our initial data shows that PSP patients make a pathological
type of eye movement, called a square-wave jerk, with higher prevalence than normal healthy subjects.
We have also developed a new (and first) objective algorithm that objectively characterizes square-wave
jerks from eye position data collected with an ocular monitor.
Chen Y, Martinez-Conde S, Macknik SL, Bereshpolova Y, Swadlow HA, Alonso J-M. Detection
Difficulty Modulates Neuronal Activity in Primary Visual Cortex. Nature Neuroscience. 11(8): 974982. 2008.
Macknik SL, King M, Randi J, Robbins A, Teller R, Thompson J, Martinez-Conde S. Attention and
Awareness in Stage Magic: Turning Tricks Into Research. Nature Reviews Neuroscience. July 2008.
Also featured in The New York Times, The Boston Globe and National Public Radio.
Troncoso XG, Macknik SL, Martinez-Conde S. Microsaccades Counteract Perceptual Filling-in. Journal
of Vision. 8(14): 1-9. 2008.
Otero-Millan J, Troncoso XG, Macknik SL, Martinez-Conde S. Saccades and Miccrosaccades During
Visual Fixation, Exploration, and Search: Foundations for a Common Saccadic Generator. Journal of
Vision. 8(14): 1-18. 2008.
Martinez-Conde S, Macknik SL. Fixational Eye Movements Across Vertebrates: Comparative Dynamics,
Physiology, and Perception. Journal of Vision. 8(14): 1-16. 2008.
Macknik SL, Martinez-Conde S. Consciousness: Neurophysiology and Visual Awareness In. [Ed.
Squire L.] New Encyclopedia of Neuroscience. 3: 105-16. Oxford Press. 2009.
Otero-Millan J, Leigh RJ, Serra A, Troncoso XG, Macknik SL, Martinez-Conde S. Objective

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Characterization of Square-wave Jerks Allows to Differentiate Between Progressive Supranuclear Palsy
Patients and Healthy Volunteers Populations. Society for Neuroscience. 38th Annual Meeting.
Washington, DC. 2008.
Otero-Millan J, Leigh RJ, Serra A, Troncoso XG, Mackink SL, Martinez-Conde S. Objective
Characterization of Square-wave Jerks Differentiates Progressive Supranuclear Palsy Patients from
Healthy Volunteers. Vision Sciences Society. Naples, FL. 2009.
Otero-Millan J, Leigt RJ, Serra A, Troncoso XG, Mackink SL, Martinez-Conde S. Objective
Characterization of Square-wave Jerks in Progressive Supranuclear Palsy Patients and Healthy Volunteers.
Vision Sciences Society. Naples, FL. 2008.
Otero-Millan J, Leigh RJ, Serra A, Troncoso XG, Mackink SL, Martinez-Conde S. Objective
Characterization of Square-wave Jerks in Progressive Supranuclear Palsy Patients and Healthy Volunteers.
Society for Neuroscience. 37th Annual Meeting. San Diego, CA. 2007.

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George R. Pettit, Ph.D.

Arizona State University
Award Amount FY08: $150,000

Molecular Targeting of Prostate Cancer Vasculature: A New Approach to Treatment
Over one million American families are vitally affected and impacted by prostate cancer. One in six
men in the United States will be diagnosed with prostate cancer in their lifetime. In Arizona in 2004,
some 4,000 new cases of prostate cancer were detected and about 600 men died from the disease. Prostate
cancer is the most commonly diagnosed non-skin cancer and the second most common cancer killer
of American men. Recent (2005) statistics indicate some 240,000 new cases diagnosed and 30,000
deaths. The generally tragic and all-too-frequently lethal outcome for prostate cancer victims will not
be alleviated until treatment approaches are greatly improved by introduction of new and more generally
curative anticancer drugs for controlling prostate cancer. Unfortunately, curative therapy in the form
of radical surgery or radiotherapy requires the disease to be confined to the prostate. Metastatic prostate
cancer is usually incurable and most men diagnosed with metastatic disease die over a period of months
to years. To further complicate the treatment problem, prostate cancer is not a homogenous disease at
the molecular level. In addition, no treatment regimen has been proven to provide a substantial
improvement in survival time and many are quite detrimental to the quality of life. Our research group
has pioneered the discovery and development of new cancer vascular targeting drugs/prodrugs, and
we are extending this very successful research focus to making improvements in the treatment of human
prostate cancer.

Richard D. Posner, Ph.D.

Northern Arizona University
Award Amount FY08: $133,111
Modeling Vulnerability of Cancer

Signal-transduction systems comprise the decision-making apparatus of cells. Many serious health
problems, including cancer, can develop when signal transduction pathways go awry. In the past decade
there has been a major effort to identify the chemical species that populate specific signaling pathways
and, for each of these species, to determine how it is regulated, with what molecules it interacts, and
its role in the signaling process. This has led to the development of a new generation of “targeted”
pharmaceuticals. As the number of identified signaling molecules has grown and new regulatory
mechanisms have been discovered, networks to describe these systems have grown exponentially in
complexity. It is no longer possible to use intuition alone to guide targeted drug discovery. This project
develops and experimentally verifies computational models of signaling networks to guide and streamline
target identification and selection, as well as affords testing of multi-agent treatment regimens for
cancer.

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Donato F. Romagnolo, Ph.D.

University of Arizona
Award Amount FY08: $49,445

Epigenetics of Breast Cancer and Chromatin Remodeling
The long-range goal of this project is to identify the factors that increase the risk of sporadic breast
cancer through epigenetic regulation, and develop dietary strategies that prevent this event. The central
hypothesis of this project is that the activation of the aryl hydrocarbon receptor (AhR) by dietary and
environmental ligands leads to epigenetic modulation of tumor suppressor and promoter genes, whereas
these effects can be prevented by dietary compounds. In year 1 of this project, we investigated the
protective effects of dietary selective AhR modulators against changes in transcription induced by AhRligands. To begin answering this question, we have investigated the molecular interactions of the AhR
and a number of transcription factors at the BRCA-1 and cyclooxygenase-2 (COX-2) promoters and
found that the regulation of BRCA-1 by estrogen required the participation of members of the
transcription factor Sp, in detail Sp1 and Sp4. This observation is important to the overall scope of
the project because the AhR physically binds to the estrogen receptor (ER) and Sp factors. This physical
interaction represents a mechanism for transcriptional repression of BRCA-1 by the AhR. Conversely,
the recruitment of the AhR to the COX-2 promoter led to activation of transcription.
We also have investigated the time-course recruitment of the AhR to xenobiotic response elements (XRE),
which are binding targets for the activated AhR. Results of DNA binding and chromatin
immunoprecipitation (ChIP) studies documented that TCDD-induced the association of AhR to XRE
found in promoter oligonucleotides from the CYP1A1 promoter selected as a control model. In
addition, we observed that the TCDD-induced binding of the AhR was reduced by small-interfering
RNA (siRNA) for th AhR. The recruitment of AhR was also reduced by cotreatment with the compound
3-methoxy-4 naphthoflavone. These data sugest that the recruitment of the AhR to target XRE is time
dependent and can be prevented by intervention with siRNA for the AhR or antagonists for the AhR.
Previous studies have shown that, unlike BRCA-1, the COX-2 gene is induced by the AhR ligand TCDD.
Results of binding studies indicated that the treatment with TCDD induced the binding of the AhR,
but this effect was reduced by cotreatment with the dietary factor 3, 3’-Diindolylmethane (DIM), a
condensation product of indol-3-carbinol (I3C) found in Brassica (cruciferous) vegetables. Results of
these studies have been accepted for publication.
Taken together, these data suggest that naturally occurring modulators of th AhR such as SIM may be
effective agents in dietary strategies targeted to modulate the recruitment of AhR to target sequences
in the BRCA-1 and COX-2 promoters. Current experiments are investigating the chromatin remodeling
events that accompany these changes.
Degner SC, Kemp MQ, Hockings JK, Romagnolo DF. Cyclooxygenase-2 Promoter Activation by the
Aromatic Hydrocarbon Receptor in Breast Cancer mcf-7 Cells: Repressive Effects of Conjugated
Linoleic Acid. Nutrition Cancer. 59(2):248-57. 2007.

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Hockings JK, Degner SC, Morgan SS, Kemp MQ, Romagnolo DF. Involvement of a Specificity
Proteins-binding Element in Regulation of Basal and Estrogen-induced Transcription Activity of the
BRCA-1 Gene. Breast Cancer Research. 10(2):R29. 2008.
Degner SC, Papoutsis AJ, Selmin O, Romagnolo DF. Dietary Targeting of Aryl Hydrocarbon ReceptorMediated COX-2 Gene Expression in Breast Cancer Cells. The Annual AICR Research Conference
on Food, Nutrition, Physical Activity, and Cancer. Washington, DC. 2008.
Degner SC, Papoutsis AJ, Selmin O, Romagnolo DF. Targeting of Aryl Hydrocarbon Receptor-Mediated
Activation of COX-2 Expression by the Indole-3-Carbinol Metabolite 3,3’-Diindolylmethane in Breast
Cancer Cells. Journal of Nutrition. In press.
Romagnolo DF. Modifying Cancer Risk with AhR Based Phytochemicals: Epidemiological and
Mechanistic Evidence. Presentation Department of Nutritional Science University of Arizona. Tucson,
AZ. 2008.

Joyce A. Schroeder, Ph.D.

University of Arizona
Award Amount FY08: $49,999

Mechanism of CD44-HA Mediated Inhibition Breast Cancer Metastasis
We have evaluated the effects of altering the main ligand for CD44, HA, in the ECM. Using HA either
embedded in the ECM (eHA), or presented in the media (sHA), we have determined that HA
differentially alters proliferation depending on its presentation in the cellular microenvironment. In
the presence of sHA, proliferation is inhibited. Conversely, when interacting with eHA, cells decreased
spreading onto collagen gels while increasing proliferation. When HA is absent from the cellular
microenvironment, cells adhere and proliferate at rates in between those seen with soluble or matrix
associated HA. The differential effects seen in the presence of sHA and eHA are mediated by ERK
and PAK, as demonstrated through the use of their inhibitors in proliferation assays, an analysis of
protein expression and activation. Overall, these results demonstrate that the manner in which HA is
presented to the cells alters adhesion, migration signaling, and proliferation. These data will be used
to design future experiments for peptide development and treatment to determine if a CD44-directed
therapy can be developed.

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Ornella Selmin, Ph.D.

University of Arizona
Award Amount FY08: $49,954

Folate as a Nutrient Competitor Against Environmental Exposure to Trichloroethylene
During the first year of the study we have bred four groups of rats using two types of folic acid
supplemented diet (either 2 or 8mg/kg), in the presence or absence (control groups) of 10ppb TCE
in the maternal drinking water. Embryos from each group were harvested at day 11, and RNA was
isolated for gene expression analysis. Preliminary analysis of the data indicates that exposure to TCE
in the presence of maternal high folate diet (8mg/kg) may reduce the number of reabsorbed embryos
when compared to the control non-exposed group animals. Future molecular analysis will reveal whether
or not this effect may lead to an increased number of neonates carrying heart defects. These results are
significant in light of the low dose of TCE used in this study and the fact that large groups of Arizonians
may be at risk from exposure to similar doses of TCE.

D. Larry Sparks, Ph.D.

Sun Health Research Institute
Award Amount FY08: $150,000
CSF Copper and Cognitive Performance

Alzheimer’s disease (AD) affects nearly 5 million Americans and 125,000 Arizonans, as a progressive
dementing disorder gradually ending in the total loss of self. The financial and emotional burden on
the caregiver (normally the spouse) of an AD patient can be staggering. Identifying a method of
predicting which individuals might develop AD could reveal a method of treating and hopefully
delaying progression or onset of the disorder. In an autopsy study we found that there is a gradual
reduction of copper levels in the cerebro-spinal fluid (CSF) as an individual coursed from normal
cognitive performance to dementia of AD. We have shown that we can quantify copper levels in human
saliva, but have yet to show that they co-vary with CSF levels. We are testing the hypothesis that
reduced copper levels in CSF/saliva are predictive of future cognitive impairment by yearly assessment
in this three-year longitudinal investigation.
Sparks DL, Ziolkowski C, Connor D, Beach T, Adler C, Sabbagh M. Copper and Cognition in
Alzheimer’s Disease and Parkinson’s Disease. Cell Biology and Toxicology. 24:426-30. 2008.

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Brent L. Vernon, Ph.D.

Arizona State University
Award Amount FY08: $150,000

Improved Materials for Endovascular Embolization
For treatment of aneurysms and arteriovenous malformations (AVM), an efficient material is needed
to block blood flow to the site. Due to its temperature-sensitive properties and wide use in the biomedical
field, NIPAAm is suitable for such applications. The structural, thermal and mechanical properties of
the NIPAAm-based copolymers were analyzed using various techniques and demonstrated promising
characteristics for embolization of AVMs and aneurysms. Due to the simultaneous chemical crosslinking
which occurs through the Michael-type addition reaction and the physical gelling undertaken at higher
temperatures as the polymer undergoes phase transition, the polymer has shown its ability to endure
stress and strain experienced in the endovascular system. Cytotoxicity studies have also demonstrated
its non-toxic effect on cells. Once tested in vivo, these materials can then be used to treat patients suffering
from endovascular malfunctions such as aneurysms and AVMs.

Danzhou Yang, Ph.D.

University of Arizona
Award Amount FY08: $50,000

Novel AP-1 Inhibition of a Highly Potent Anticancer Drug XR5944
XR5944 is a novel cytotoxic agent with exceptional anti-tumor activity against a range of human and
murine tumor models both in vitro and in vivo. The objective of this project is to characterize the novel
AP-1 inhibition of XR5944. We have shown previously that the in vitro DNA binding of the c-June
AP-1 protein is inhibited by XR5944. Now, our electrophoretic mobility shift assay (EMSA) results
demonstrated that XR5944 remarkably inhibits the DNA binding of AP-1 proteins from nuclear
extracts. Using mouse keratinicytes, we have shown that XR5944 is capable of inhibiting UVB induced
transcriptional activity of AP-1 in cells, whereas the level of AP-1 proteins is not changed. AP-1 is the
key family for transducing multiple signals for cell proliferation, thus targeting AP-1 by a small molecule
drug can be an effective approach to inhibit cancer cell growth. Our research will be useful to identify
a potential anticancer drug target.

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Daniela C. Zarnescu, Ph.D.

University of Arizona
Award Amount FY08: $49,999

Mechanisms for Local Translational Control in Drosphila Neural and Germ Stem Cells Gene
Fragile X syndrome is the most common form of inherited mental retardation and affects one in 4,000
males and one in 8,000 females in the state of Arizona. The disease is due to deficits in Fragile X
protein (FMRp) function. Here we hypothesize that FMRP functions in stem cells by controlling
specific target mRNAs. To test this, we investigated whether FMRP loss affects the development of
germ and neural stem cells. We are using Drosophila as a model system due to its powerful genetic and
molecular tools. During the first year of the project we made significant progress toward our goals. We
discovered that germ and neural stem cells lacking FMRp overproliferate and produce more cells. Our
data suggest that FMRP may control proliferation via a ubiquitin ligase enzyme, Cbl. These results
identify new pathways affected by FMRP and have the potential to be used for new therapeutic
approaches in the future.
Zarnescu D. Fragile X Protein Controls the Proliferation and Differentiation of Neural Stem Cells.
Annual Drosophila Research Conference. San Diego, CA. 2008.

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Section D
New Contract Awards
Beginning in FY 2009

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70

Mohamad Azhar, Ph.D.

University of Arizona
Award Amount FY09: $50,000
Role of TGF-beta Ligands in Aortic Aneurysm

An aneurysm is a localized, blood-filled dilation of a blood vessel caused by disease or weakening of
the vessel wall. Aneurysms most commonly occur in the aorta (the main artery coming out of the heart).
Aortic aneurysms can occur in the abdomen, chest and aortic root of the heart. The bulge in a blood
vessel can burst and lead to death at any time. Aneurysms are a common finding in patients of Marfan
syndrome (MFS, MFS2), familial thoracic aortic aneurysms and dissections (TADD) and Loeys-Dietz
syndrome (LDS), and they are associated with tobacco smoking and with gene mutations in TGF-β
receptors (i.e., TGFBR2 or TGFBR1). Based on the positive benefits of Losartan therapy (which lowers
TGF-β activity) in Fibrillin-1 mutant mice (mice which model MFS), a phase III clinical trial is being
currently conducted by the Pediatric Heart Network to determine whether blocking TGF-β activity
by Losartan can prevent aneurysm. One of the ways Losartan blocks TGF-β activity is to reduce
expression of TGF-β ligands. Therefore, it is important to delineate the function of individual
TGF-β ligands in the pathogenesis of aneurysm.
The major goal of this proposal is to identify the specific function of TGF-β ligands in aortic aneurysm
disorders. Extensive experimentation by others in Fibrillin-1 mutant mice has found that these mice
exhibit enhanced TGF-β activity in the vessel wall due to the breakdown of wall architecture, and that
this increased TGF-β activity causes aneurysm in these mice. It is not known which TGF-β ligands
contribute to this increased TGF-β activity and aneurysm in these mice. Our preliminary studies
suggest that the TGF-β2/ TGF-β3 doubly-deficient (DKO) embryos develop aortic aneurysm and die
at around 14.5 day of gestation. The proposed hypothesis is that TGF-β2 and TGF-β3 are both required
for protection against aneurysm, whereas excess TGF-β1 causes aortic aneurysm. Combinations of
TGF-β deficiencies in the mouse and pharmacological approaches will be used to exacerbate or rescue
aortic aneurysm by systematically altering dosage of TGF-β activity in order to determine the effects
of the individual TGF-βs.
Objective 1) Determine the molecular, cellular and developmental aspects of aortic aneurysm in
TGF-β2/ TGF-β3 DKO mice to assess the underlying mechanisms by which these ligands protect
against aortic aneurysm.
Objective 2) Determine whether enhanced TGF-β activity mediates aneurysm in DKO mice by
pharmacologic treatment of female pregnant mice carrying DKO embryos with inhibitors of TGF-β
activity (i.e., Losartan, TGF-βR1 inhibitor and TGF-β neutralizing antibodies).
Objective 3) Generate TGF-β1/Fibrillin-1 DKO mice to determine whether a reduction in TGF-β1
rescues aortic aneurysm in Fibrillin-1 mutant mice.

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These studies will determine the underlying molecular pathogenesis of aneurysm disorders and have
implications in developing safe therapies for aneurysm disorders. These studies are highly significant
to the biomedical issues facing Arizona because tobacco-caused cardiovascular diseases remain the
leading cause of death of Arizonans. Also, aneurysms are more common in the elderly, and Arizona
has a high percentage of population 65 and older.

Ross Bremner, M.D., Ph.D.

St. Joseph’s Hospital
Award Amount FY09: $50,000

Predictors of Therapy Response in Adenocarcinoma of the Lung
Non-small cell lung cancer remains the leading cause of cancer death in industrialized countries and
yet lags behind in preclinical models and genomics investigations. In Arizona, there are 2,760 new
cases of lung cancer each year of which 2,550 men and women will die of lung cancer. The last decade
has seen a shift in the most common histologic sub-type of lung cancer from squamous cell to
adenocarcinoma. For unknown reasons, the incidence of adenocarcinoma of the lung in non-smoking
women is escalating. Unfortunately, lung adenocarcinoma is often a metastatic process at discovery,
even if the primary cancer is small. Surgical cure rates for early lung cancer are only in the range of
60-70% and chemotherapy has historically been disappointing, with only about 25-30% of cancers
showing any meaningful response. Recently new small molecule biologic therapies have demonstrated
promising activity against cancer, suggesting a break through in cancer treatment by matching a
targeting agent to a specific aberrant molecular pathway. As more targeting agents are developed and
as tumor-specific targets are identified, systems to align these agents to proper application will greatly
accelerate and refine personalized medicine.
Our overall hypothesis is that a molecular signature in patient tumors may direct optimal or effective
therapy selection, thereby enabling personalized treatment planning. In accordance to Arizona’s Bioscience
Roadmap, this collaborative interface between St. Joseph’s Hospital and the Translational Genomics
Research Institute will advance the science and understanding of lung cancer and build a strong
collaboration for translating laboratory discoveries into clinical care, treatment, and commercialization

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of technology in the state of Arizona.
The long-term goal of this project is to develop more effective therapies against lung adenocarcinoma
based on molecular features in patient specimens. The objective of this project, and an important step
toward accomplishing our long-term goal, is to implement a collaborative clinical and laboratory
network for lung tumor tissue collection, which will foster the development of xenograft models for
biological and therapeutic testing coupled to proficiency in expression profiling for guidance of
individualized therapy of lung adenocarcinoma. The strategy for this research is to develop, test, and
implement genomic profiling of lung adenocarcinoma and develop biological models for personalized
medicine.
To accomplish the objectives of this project, we will pursue the following specific aims:
1) Establish a pre-clinical xenograft model for lung adenocarcinoma and determine whether molecular
profiling can identify predictors of tumor response or non-response to conventional chemotherapeutic
agents. We will operate a successful collection, preservation, and serial propagation model of lung
adenocarcinoma suitable for follow-on tumor biology, molecular genetic, and therapy testing experiments.
We propose to establish 3-4 primary lung adenocarcinoma xenografts per year suitable for serial
propagation as subcutaneous tumors in mice. We will next use whole genome expression profiling of
xenografts to discern whether molecular profiling can predict / guide therapy selection.
2) Validate candidate genes discovered in Aim #1 and determine the cellular and biochemical mechanisms
of action of these genes in relation to the responses to chemotherapeutic treatment. Clinical associations
between therapy responses and gene candidates identified in Aim #1 will be evaluated by comparing
the differential expression of these genes in the therapeutic responders and non-responders xenografts.
Quantitative RT-PCR will be used to either eliminate candidate genes or to advance them to mechanistic
experiments. Specific inhibition or activation strategies (antibodies, siRNA, or transfection of identified
genes, respectively) will be used to determine the function of the genes in therapeutic responses.
Additionally, we will develop a tissue microarray using archival human lung adenocarcinoma specimens
to survey patterns of markers for tumor progression and therapeutic selections.

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Michael R. Caplan, Ph.D.

Arizona State University
Award Amount FY09: $50,000

Reverse Engineering the Basement Membrane
Many medical devices designed to address cardiovascular problems fail due to material-host interactions,
in particular inflammation. Examples include artificial vascular grafts, stents, pacemaker leads, heart
valves, and almost all other blood-contacting systems. These are examples of pathological cellular
response to materials, but there is a material in our bodies that for the most part works well for decades.
The material is the basement membrane which is a material made mostly of proteins to which vascular
endothelial cells adhere in normal blood vessels. These endothelial cells receive cues from the basement
membrane and their other surroundings that cause them to respond by not recruiting inflammatory
cells or platelets except in pathological situations. What is it about this material that elicits desirable
responses from endothelial cells whereas synthetic materials elicit undesirable responses? Can doctors
and engineers use that knowledge to trick cells into responding to synthetic materials in a desirable
way? To answer these questions, it is essential to understand how these cells sense their surroundings
and convert those sensations into gene regulation.
Several aspects of this project are of great importance to the state of Arizona and Arizona residents.
First, improved materials for medical devices, particularly cardiovascular devices, would directly help
many Arizona residents due to the rising rate of cardiovascular disease. Secondly, as design principles
for creating better materials are discovered, it is likely that graduates trained in this work will work for
Arizona-based companies such as Bard Peripheral Vasculature and W.L. Gore, thus building Arizona’s
biomedical industry. Finally, this research will cement collaborations among ASU, University of Arizona,
and the Translational Genomics Institute forged to develop preliminary data for this proposal. This
collaboration has potential to provide Arizona with a center of expertise in systems biology applied to
biomaterial design which does not currently exist anywhere else in the world. In these ways, the research
can enhance the health, economy, and prestige of the state of Arizona and Arizona residents.
In this study we propose to systematically control the stiffness and protein composition of a material
and then study the responses of human umbilical vein endothelial cells that are brought into contract
with those materials. We will measure the activity of six or more molecules that transmit sensation
from the cell’s surface to its nucleus (each representative of a distinct signaling pathway) for cells in
contact with materials of which we have varied stiffness and protein composition. To aid in interpretation
of the data, we will use principal component analysis and partial least squares regression which are
well-established techniques for making sense of highly complex, multivariate systems. Using these
techniques we will correlate material properties with the signals that they activate. We hypothesize that
unique material properties cause a unique pattern of cell signaling which in turn controls cellular
production of molecules necessary for recruitment of inflammation. This hypothesis will be tested by
completing three aims: 1) quantify signaling cascade activation when cells contact materials; 2) identify

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cell behaviors that result from these activated signaling cascades; and 3) study the role of individual
signaling pathways via inhibitors of signaling molecules.

Qin M. Chen, Ph.D.

University of Arizona
Award Amount FY09: $50,000
Oxidant Induced c-Fos Phosphorylation

Tobacco smoking causes an increased risk for coronary heart diseases. Arizona is among the states that
have the highest population of tobacco smokers. Smoking produces oxidants. In addition, oxidants
are produced as byproducts of aerobic metabolism and during ischemia-reperfusion. Oxidants can
damage macromolecules or cells inside our body. But recent studies with antioxidant administration
have generated controversial results. It is not known at mechanistic levels how oxidants may cause
heart diseases and whether antioxidants can prevent heart disease due to smoking. Cardiomyocytes are
the major type of cells in the heart and are responsible for contractile function of the heart. Enlargement
of cardiomyocytes is often observed in failing hearts. It is known that hypertension can cause
cardiomyocytes to enlarge. This is usually resulting from the action of small peptide endocrine factors,
such as angiotensin II and endothelin-1, on the heart cells. We find that low to mild concentrations
of oxidants cause cardiomyocytes to enlarge. We are trying to find whether there is a central switch,
such as c-Fos transcription factor, within cardiomyocytes that controls cell enlargement.
While studying the mechanism of oxidant effect on cardiomyocytes, we found that oxidant causes
changes in a certain transcription factor. One component of AP-1 transcription factor, c-Fos, undergoes
phosphorylation when cells encounter oxidants. We are trying to understand the upstream molecules
regulating c-Fos phosphorylation and downstream consequence of c-Fos phosphorylation. By focusing
one molecule, e.g. c-Fos, at a time, we can trace back to the question whether or not this molecule
serves as a central switch that controls cardiomyocyte enlargement and whether this molecule can serve
as a target for curing certain types of heart disease associated with oxidant overexposure, such as in the
cause of tobacco smoking. We have come up with three specific aims to test the hypothesis that H2O2
induces c-Fos phosphorylation at specific amino acid residues and phosphorylation of c-Fos at these
residues increases the stability of c-Fos protein and, therefore, the activity of AP-1 transcription factor.

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Cheryl D. Conrad, Ph.D.

Arizona State University
Award Amount FY09: $49,940

Stress and Estrogen Actions in the Female Hippocampus
Many psychiatric conditions such as Alzheimer’s disease (AD), schizophrenia, and major depressive
disorder (MDD) show changes in the brain that are most prominent in the hippocampus, a region
important in learning and memory. Projections for the year 2020 indicate that MDD will be the
leading cause of disability and disease burden throughout the world, and this should apply to Arizona
as its population and retirement communities continue to grow.
MDD and chronic stress show changes in similar brain regions, circuitries and mediators, especially
within the hippocampus, suggesting that MDD and chronic stress may share common mechanisms.
Moreover, many symptoms in AD, schizophrenia and MDD are triggered or exacerbated by stress.
Work from our lab and others show that chronic stress in males causes hippocampal dendritic retraction
which is characterized by reduced dendritic complexity of hippocampal neurons. This chronic stressinduced hippocampal dendritic retraction is associated with impaired hippocampal function, such as
poor memory, and increases the susceptibility of the hippocampus to metabolic challenges. These
metabolic challenges may include ischemia/stroke (blood flow obstruction), hypoxia (lack of oxygen),
and hypoglycemia/hyperglycemia (abnormal sugar levels). While all of these metabolic challenges can
be damaging by themselves, these events become even more crippling under conditions that the
hippocampus is already compromised from AD, schizophrenia MDD and chronic stress. Therefore,
delineating the mechanisms by which the hippocampus can be protected under compromised conditions
will be essential for protecting it against further damage.
The problem is that the majority of research on MDD and stress focus on male subjects, but females
are more than twice as likely as men to develop MDD. In our research, chronic stress exacerbates
hippocampal damage caused by a neurotoxic insult in males, but does not exacerbate hippocampal
damage in females. Why females are protected from further damage following chronic stress has not
been studied and is the purpose of these studies. However, we hypothesize that estrogen may be
neuroprotective against chronic stress actions for two main reasons. 1) Pilot data show that estrogen
protects against chronic stress-induced hippocampal dendritic retraction in females. 2) The presence
of hippocampal dendritic retraction has been a marker for hippocampal susceptibility to a neurotoxic
challenge. Therefore, conditions that prevent hippocampal dendritic retraction may also prevent the
detrimental effects of chronic stress on the structure of the hippocampus.
The goal of these studies is to determine whether estrogen and the estrogen receptor protect females
against chronic stress-induced exacerbation of hippocampal damage caused by a neurotoxin challenge
using ibotenic acid (IBO).
We hypothesize that estradiol protects against chronic stress-induced hippocampal vulnerability to

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neurotoxin exposure. Objective 1 is to examine whether estrogen mediates the neuroprotective effect
within the hippocampus that is observed in chronically stressed females in response to an Ibotenic acid
(IBO) challenge. Objective 2 is to determine the involvement of estradiol receptors in the neuroprotective
effects against chronic stress-induced exacerbation of hippocampal damage following an IBO challenge
in females.

Keith D. Coon, Ph.D.

St. Joseph’s Hospital
Award Amount FY09: $47,749

Perioperative Strategies to Improve Outcomes in Patients with NSCLC
Non-small cell lung cancer (NSCLC) is the most common cause of cancer death in the western world.
Most treatments have not been very effective as demonstrated by the overall survival rate of 15%.
There are 2,760 new cases of lung cancer in Arizona annually, of which 2,550 men and women will
die. If detected early, surgical removal of the tumor can increase a patient’s long-term survival rate to
60%-70%, but many will still recur with distant metastases. This rate of recurrence implies the presence
of lingering cancer cells at the time of surgery, and the severity of the surgical procedure has been
shown to impact the incidence and magnitude of recurrence. Historically, there has been no therapy
given around the time of surgery for fear of interfering with a successful surgical outcome; however,
it has been suggested that perioperative treatment with an anti-cancer agent might reduce the risk of
recurrence. One promising group of anti-cancer agents that could potentially be used in this fashion
is cyclooxygenase-2 (COX-2) inhibitors. The COX-2 inhibitor celecoxib has been shown to have anticancer effects and does not demonstrate significant side effects, especially when used for limited periods
of time. The use of microarrays for studies of gene expression has increased the accuracy of disease
characterization in many cancers including NSCLC. However, this valuable tool has not yet been
applied to characterizing the effects of surgery on the potential to develop distant metastases or assessing
the response to therapeutics given around the time of surgery.
We hypothesize that surgical resection of NSCLC tumors produces discernible changes in gene expression
that create a local and/or systemic microenvironment that is conducive to both the recurrence of the

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primary tumor and the ability of the primary tumor to metastasize to a distant locale, thus promoting
further tumorigenesis. We further hypothesize that perioperative administration of celecoxib around
the time of the introduction of surgical stress will demonstrate a significant inhibition of these
tumorigenic effects. Our goal is to determine the effect that surgery has on gene expression, whether
these effects are tumorigenic, and whether perioperative administration of celecoxib can counteract
these changes.
It is our objective to make Phoenix, Arizona a nationally-known clinical and research hub for thoracic
disease and we are uniquely positioned to accomplish this. St Joseph’s hospital and the recently developed
Heart and Lung Institute has the only dedicated thoracic surgical oncology division in Phoenix and
has the only CyberKnife in Arizona. The thoracic surgeons routinely perform minimally invasive
(VATS) lobectomies, which is usual for this city, and St Joseph’s has one of the largest CyberKnife lung
cancer programs in the country. Consequently, in combination with our existing genomics expertise,
we have an exclusive opportunity to study the effects of these innovative procedures at the molecular
level. Further, our background in the study of inflammation and the cyclooxygenase enzyme enables
us to perform a translational study in our patient population that as the potential to provide unique
insights into not only the tumorgenic effects of surgery, but the potential to overcome these effects
with a non-toxic therapeutic agent, in this case celecoxib. We expect the results from this study to provide
a fertile foundation to further study the “perioperative period” and to improve the outcomes for our
patients undergoing surgery for cancer. Though celecoxib has been tested extensively as an anti-cancer
therapeutic in vitro and in animals, this study represents the first attempt to utilize a perioperative
treatment regimen of celecoxib in a randomized, prospective study of human subjects to directly
minimize the reported effects of surgery-induced promoters of metastases and interrogate the changes
induced by both surgery and celecoxib treatment at the molecular level via microarray-based gene
expression analyses. This study will provide important information as to the molecular mechanism that
underlies the high incidence of recurrence/metastasis observed in lung cancer patients. It also has the
potential to move rapidly into clinical trials, resulting in a potential cancer treatment that could be
implemented in the clinic in a relatively short amount of time. This treatment has the added benefit
of being inexpensive with potentially little to no side effects. Though the hypotheses being tested in
this investigation will need to be further validated in a larger cohort of patients, validation of this novel
therapeutic avenue could have tremendous impact on not only the surgical treatment of lung tumors,
but on surgical treatment for other cancers, and as such, represents an exciting potential advance in
our approach to cancer therapy. In summary, utilizing well-established genomic strategies, this project
will address novel questions relating to patient outcome following surgical removal of cancerous lesions
via three standard procedures and has distinct potential to have significant impact on the health of
cancer patients as well as surgical patients in general.

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Torsten Falk, Ph.D.

University of Arizona
Award Amount FY09: $50,000

Transplantation of Adult RPE Cells as a Treatment for Parkinson’s Disease
Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting the senior
population in Arizona (2% of the population over 65 years of age). At the present time, treatment of
this movement disorder is inadequate. Developing new treatments for PD has been identified as a major
focus area defined by the Arizona Bioscience Roadmap report commissioned by the Flinn Foundation.
This project will test a novel cell-based therapy approach to the treatment of PD. PD occurs due to
the loss of a small but important population of brain cells that produce the chemical messenger know
as dopamine. These cells are critical for the normal control of movement. Patients with PD can be
adequately treated with oral dopamine replacement therapy for about 5 years, but after this time the
response to oral medications becomes inadequate and this has no effect on the ongoing process of cell
loss and degeneration. This is in part due to the fact that oral medications cannot penetrate into the
brain where they are needed and in part due to the ongoing loss of the normal cells that produce
dopamine. In this proposal, we will explore the possibility of transplanting dopamine producing cells
into the brain that will act as a direct source of dopamine. In addition, the cell type which we are studying,
known as “rentinal pigment epithelium” or RPE cells, may have the ability to slow or prevent the
ongoing degeneration of the normal dopamine-producing cells in the brain. The RPE cells are obtained
from eyes donated to the eye bank from deceased donors. In the future, we could also obtain RPE
cells by taking a sample from a patient suffering from PD and later transplant the patient’s own cells
into the brain. RPE cells are not stem cells and can be obtained from adult sources.
We hypothesize that RPE cells can produce both dopamine and a neuroprotective factor called PEDF
that can prevent the loss of dopamine-producing neurons in Parkinson’s disease. Early clinical trials
have already shown that RPE cells can provide dopamine and help with the symptoms of PD. In this
study our goal is to test whether the cells can also prevent the ongoing loss of dopamine producing
cells. When successfully complete, this proposal will answer several important scientific question
regarding RPE cells. These are:
1) What chemical factors do RPE cells produce that protect dopamine-producing cells from Parkinson’s
disease?
2) Do RPE cell lines derived from different donors produce different levels of these protective factors?
3) Can the protective factor known as PEDF (which is produced from RPE cells) protect dopamine
cells from experimental Parkinson’s disease? If so, what dose of PEDF is necessary?
4) Can RPE cells provide the necessary dose of PEDF to protect dopamine cells?
Once this information has been obtained, we will be in a position to further develop this project for
use in a clinical trial.

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Hanna F. Fares, Ph.D.

University of Arizona
Award Amount FY09: $50,000
Deciphering Endocytosis in Multicellular Eukaryotes

Endocytosis is used for the uptake and processing of nutrients. Endocytosis is also used to regulate
other essential cellular functions. At least 70 inherited human diseases result from defects in endocytosis.
Deregulation of endocytosis also plays a causative role in cancer and can contribute to different aspects
of aging and to the pathogenesis of some age-related disease. Finally, many bacterial and viral pathogens
utilize the endocytic machinery to invade cells. Treatment strategies for various diseases have focused
on endocytosis as a vehicle to deliver therapeutic substances, especially for the treatment of neurological
defects where the substances have to cross the blood-brain barrier.
Traditionally, studies on endocytosis have been done either in mammalian tissue-culture cells or using
genetic approaches in the unicellular yeast. We decided to use the worm Caenorhabditis elegans as a
model system to study this process because C. elegans allows a level of sophistication in genetic analyses
not available with vertebrates. Studies in C. elegans have been instrumental for identifying and analyzing
the molecular pathways that regulate central conserved processes like aging, cell death, and neurobiology
and behavior.
We have established a system to study endocytosis in C. elegans and have shown its effectiveness by
identifying and characterizing novel proteins that regulate this process specifically in multicellular
eukaryotes, worms and humans. This has allowed us to propose novel mechanisms that regulate
endocytosis and to provide a cell biological explanation for the symptoms seen in various human
diseases, including Myotubular Myopathy, Charcot-Marie Tooth syndrome, and the lysosomal storage
disorder Mucolipidosis type IV. We have also used our system to identify potential leads for the
treatment of Mucolipidosis type IV. Continuing studies on endocytosis will yield a more detailed
understanding of its functions and will suggest novel treatments and applications through modulations
of its pathways.
It is estimated that 2% of all cellular proteins regulate endocytosis in a given cell. This translates to
400-600 proteins in worms and humans. Yet only a small fraction of these proteins have been identified
and are being studied. The long-term goal of this work is to fully understand how endocytosis is
regulated in multicellular eukaryotes. This requires that we identify all of the proteins that are involved
in this process. We will use the system we have established in C. elegans to identify additional proteins
that are used to regulate endocytosis in multicellular eukaryotes. We will also use our assays to characterize
the functions of the identified proteins, which will allow us to construct more elaborate models of this
complex process. These studies will provide more avenues for the treatment of human diseases and
infections through modulations of the activities of newly identified regulators of endocytosis. We will
also use our system to understand the cell biological basis for endocytosis-related diseases in humans
and to identify possible therapies.

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Sourav Ghosh, Ph.D.

University of Arizona
Award Amount FY09: $50,000

Cell Polarity Regulation During Differentiation of Embryonic Stem Cells
More than 600 disorders afflict the nervous system. Well known are disorders such as stroke, epilepsy,
Parkinson’s disease, autism, etc. Motor Neuron Diseases such as ALS are a group of progressive
neurological disorders that destroy cells that control essential muscle activity such as speaking, walking
and swallowing. Eventually, the ability to control voluntary movement can be lost. In adults, symptoms
often appear after age 55 and are thus of particular concern for states such as Arizona. In children,
particularly in inherited or familial forms of the disease, symptoms can be present at birth or appear
before the child learns to walk. Many other neurological disorders are rare, known only to the patients
and families affected. Neurological disorders strike an estimated 0.8 million Arizonans each year,
exacting an incalculable personal toll and an annual economic cost of millions of dollars in medical
expenses and lost productivity. Is there a treatment? There is no cure or standard treatment. Prognosis
varies depending on the type of disease and the age of onset; however, many cases are typically fatal.
There are many prospective applications for using embryonic stem (ES) cells to treat neurological
diseases and injuries; however, a critical barrier to progress is the inability to efficiently and reliably
enhance neuron generation from these cells while simultaneously minimizing the risks of abnormal
proliferation and cancer. Understanding the molecular processes will eventually lead to improved
techniques for deriving neurons from ES cells for regenerative medicine and improve the quality of
life for Arizonans. The training of scientists who will serve as future educators and researchers, and
potentially novel intellectual property essential to creating high quality jobs in biotechnology and
pharmaceutical industries will be added benefits.
aPKCζ gene codes for an enzyme are essential for the three-dimensional structural organization and
architecture or ‘polarity’ of cells. The main goal of this project is to define this enzyme-directed, essential
regulatory step that may operate to control the acquisition of neuronal fate from ES cells. Because so
little is known about how ES cells differentiate, this project will focus on understanding how aPKCζ
function and polarity changes as a single neuronal subtype–motor neuron–is generated. Our hypothesis
is that manipulation of aPKCζ gene will enhance motor neuron generation. Thus, our study will be
directly applicable to ES cell use for treating motor neuron diseases. Nevertheless, the mechanisms that
operate to control motor neuron formation are also likely to be relevant to many other neurons; and
thereby, our study will serve as a platform for treating a wide range of neurological diseases. The flip
side of the coin is that stem cells, in many ways, resemble cancer seed cells and alterations of aPKCζ
activity may cause cancer. We will investigate this possibility, study the molecular mechanism and
consequently reduce this risk. Over the long term we plan to identify small compounds (drugs) targeting
this enzyme. Drugs that enhance neuron formation are likely to improve scientists’ ability to experiment
with ES cells and create in vitro models for studying neurological diseases. These drugs may also be
used to stimulate endogenous stem cells within adults to self-repair damaged areas of the brain, while
at the same time reducing the risk of inducing cancer.

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Steven Goldman, M.D.

Southern Arizona VA Healthcare System
Award Amount FY09: $50,000

Seeding Fibroblast Patch for Chronic Heart Failure
This project is designed to help treat patients with heart failure after a heart attack. When patients
have a heart attack, the blood vessel that supplies the heart, the coronary artery, is blocked or occluded
and part of the heart muscle dies. If we cannot open the artery or there is a lot of other damage to the
heart, the patients goes on to develop heart failure. Although there are good medical treatments for
heart failure, these treatments can not increase blood flow or add new heart cells in a damaged heart.
There is currently a lot of research interest in developing ways to put new cells in a damaged heart,
but to-date this work has been disappointing in large part because when new cells are injected into a
damaged heart, most of the injected cells do not survive. Our plan is to create a new blood supply in
the damaged heart and then transplant new heart cells. We will use a 3-dimensional fibroblast construct
(3DFC) matrix graft or patch that was, in part, developed at the University of Arizona. With the new
blood supply, we can then put new heart cells into the damaged heart and these cells will survive. We
have preliminary data in a model of acute myocardial infarction or heart attack with this patch that
show new blood vessel growth, improved blood flow and better heart function. The purpose of this
project is to explore the use of this 3DFC patch in a rat model of chronic heart failure. We will use
this 3DFC patch as a delivery system, and we will seed the patch with cardiac stem cells or new heart
cells. Thus we will be able to insure that the new heart cells will survive because these new cells will
have a blood supply and a matrix support system.
The newest treatment for acute myocardial infarction (MI) and heart failure is direct injection of stem
cells into the damaged heart. Although the pre-clinical data are very encouraging, results from clinical
trials have been disappointing. The explanation for the lack of success in clinical trials is not clear. Most
investigators believe the cells themselves do not improve left ventricular (LV) function because majority
of transplanted cells do not survive after injection. Injecting cells directly into an injured heart does
not work because this damaged tissue will not support new cell growth; the blood supply is inadequate
and there is no support matrix for cell attachment and growth. We have a new approach to cell-based
therapy for heart failure using a viable 3-dimensional fibroblast construct (3DFC) matrix patch
implanted on the infarcted heart. Our data show that this 3DFC matrix patch improves LV function
and myocardial blood flow while decreasing remodeling in acute MI. Although these data are promising,
the real need is to develop a new treatment for chronic heart failure, not acute MI. This project develops
a new treatment for chronic heart failure using the 3DFC seeded with cardiac stem cells.
Hypothesis: Use of a viable 3-dimensional fibroblast construct seeded with cardiac stem cells will
improve myocardial perfusion, reverse maladaptive LV remodeling, and improve LV function in chronic
heart failure after myocardial infarction.
Objective 1) Define changes in myocardial blood flow, LV remodeling and LV function after implanting

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the 3DFC patch onto the infarcted myocardium in a rat model of chronic heart failure.
Objective 2) Determine if seeding the 3DFC with cardiac stem cells improves LV function and decreases
LV remodeling in chronic heart failure.
Objective 3) Isolate and characterize the properties of the newly formed myocytes by measuring myocyte
shortening the Ca+ transients in the transplanted cardiac stem cells.

Stephen Helms Tillery, Ph.D.

Arizona State University
Award Amount FY09: $50,000

Role of The Basal Ganglia In Learning To Control Neuroprosthetics
The basal ganglia are a set of forebrain structures that are known to be involved in both the control
of movement and in reinforcement driven learning. While elegant work has shown signals in basal
ganglia that convey information about reward, most of the neuronal activity in basal ganglia that is
observed during movement is largely similar to neuronal activity that can be observed in motor cortical
areas. This has made it difficult to discern the role of basal ganglia in motor learning. We have embarked
on a series of studies in our laboratory on how the brain learns to control neuroprosthetic systems,
with a special emphasis on probing the limit of the brain’s ability to adapt to novel control algorithms.
Literature on basal ganglia and motor learning suggest that the basal ganglia likely will play a significant
role in modifying signal processing within the central nervous system enabling control of these systems.
In the research proposed here, we will record the activity of neurons in three nuclei of the basal ganglia,
the putamen, globus pallidus pars externa, and globus pallidus pars interna, as an animal learns to control
a neuroprosthetic system from cortical signals. We expect that signals within these structures will
parallel learning curves, with activity in striatum deviating from the movement related signals typically
seen. This is particularly the case since our neuroprosthetic tasks are performed with no overt movement.
Our overall goal in this research is to gain a more thorough understanding of how the basal ganglia
participate in reward-driven learning. We have postulated that the basal ganglia acts as a system to a)

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identify, and b) amplify patterns of cortical activity that have become associated with rewards. This
hypothesis is difficult to evaluate in standard movement tasks because movement related signals
dominate within those parts of the basal ganglia which interface to motor cortical areas. Our specific
goal here is to take advantage of our experience in brain machine interface to require learning in motor
cortex that is independent of movement. Our hypothesis is that signals in the putamen early in the
process of learning will parallel the learning rather than the actual output of cortex that is controlling
the prosthetic system. This contrasts with later in learning, where the neuronal activity in putamen
particularly will come to more closely resemble activity the cortical signals which are driving the
prosthetic system. Thus, our objective is to use this entirely novel learning environment as a probe for
neural processes which underlie reinforcement driven learning.

Jui-Cheng Hsieh, Ph.D.

University of Arizona
Award Amount FY09: $49,999

Functional Analyses of the Mammalian Hairless Protein
Since the hairless gene (Hr) was cloned in 1996, the functions of hairless protein have not and cannot
be predicted on the basis of homology. Its amino acid sequence is not related to any known protein
with the exception of six cysteine residues in central region that have been proposed to form a DNAbinding zinc finger. The autosomal recessive gene Hr is responsible for the complete hairlessness in
mice homozygous for this gene. In addition to the skin disorders, the Hr mutant mice also displayed
some defects in neuronal morphology and inner ear. Despite the importance of hairless function in
the skin and brain, very little is known about its biomedical properties such as DNA-binding capacity,
heterodimeric partners, phosphorylation sites by target kniases, the target ligands, etc. One of our
major difficulties in the field of Hr studies is the limited availability of sufficient quantities of this large,
labile protein. Therefore, how to obtain the enough quantities of purified hairless protein becomes an
urgent issue. Previous reported repressors such as N-CoR and SMART inhibit their target proteins,
but we failed to observe their transrepression for VDR. Recently, we found that the 1,25(OH) 2D3VDR-mediated transactivation is strikingly inhibited by coexpression of rat Hr corepressor to inhibit
VDR. It is noted that Hr becomes the only found repressor of VDR action. Vitamin D has been

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reported to be involved in the development of many diseases including osteoporosis, colon and breast
cancers. It raises the questions about how Hr is involved in this 1,25(OH)2D3 signaling transduction.
If successful, the project will create a new critical mass of information of how Hr transpresses its target
genes and target proteins.
We have previously shown that Hr functions as a corepressor for vitamin D receptor (VDR) transactivation
in COS-7 cells and keratinocytes (Hsieh et al., JBC 278: 38665-74, 2003). Hr interacts directly and
selectively with VDR as demonstrated at GST pull down assays. Further, like other nuclear transcription
factors, Hr contains a putative DNA-binding zinc-finger motif via six conserved cysteine residues.
Based on these observations, an attractive hypothesis is that Hr binds directly to DNA and displaces
VDR from its vitamin D responsive element (VDRE). However, there is as yet no evidence that the
Hr protein can bind to DNA. The first objective in this project is to determine whether Hr binds to
DNA including the well-characterized VDREs, thyroid hormone responsive elements (TREs) and
unknown DNA motifs. We have been interested in studying the negative gene regulation mechanism
of VDR. This Hr-mediated transrepression on VDR mechanism is important because of the wide
prevalence of 1,25(OH)2D3-VDR action in many tissues and organs such as skin, intestine, kidney,
brain, heart, bone, etc.
Many proteins involved in gene regulation have all been found to be phosphoproteins, including
thyroid hormone receptor, VDR, estrogen receptor. In the case of VDR, protein kinase C (PKC)
phosphorylates VDR at serine-51 and significantly reduced DNA-binding activity of VDR, while
serine-208 is the target site for casein kinase II (CK-II) and boosts VDR transactivation. Therefore,
considering the important influence of phosphorylation in Hr, the second aim of the project is to
determine the phosphorylation sites of Hr. Our immediate plan includes the purification of large
quantities of homogeneous Hr protein for molecular biological characterization and the identification
of Hr phosphorylation sites. This project is designed to provide insight into the architecture of Hrbinding DNA and the functional relevance of Hr phosphorylation sites. The goals of this proposal are
to 1) study Hr DNA binding capacity and 2) identify Hr phosphorylation sites and examine their
potential functional roles.

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Leland S. Hu, M.D.

St. Joseph’s Hospital
Award Amount FY09: $49,500

Distinguishing Post-Treatment Radiation Effects From Glioma Recurrence Using Dynamic
Susceptibility Contrast (DSC) MRI
A number of new and existing therapies can help maximize patient survival following initial treatment
of high grade gliomas. Applying the appropriate treatment plan relies on accurate distinction between
tumor regrowth and post-treatment changes. Accurate diagnosis requires surgery since current imaging
tests are not sufficient. However, development of specialized imaging tests can vastly improve accuracy
and may help forgo the need for invasive procedures. Dynamic Susceptibility Contrast (DSC)-MRI
is a specialized imaging test which provides information about tissue blood flow and can improve noninvasive detection of tumor growth. The preliminary results are very promising but further work is
needed. The overarching goal of this pilot study is to establish DSC-MRI as a non-invasive diagnostic
tool which provides accurate treatment planning for tumor patients.
Present evidence suggests DSC-MRI can exploit the inherent differences between high blood flow in
tumor growth and low blood flow in post-treatment tissue to provide measurements which distinguish
the two entities; however, the DSC-MRI measurements must first be validated by directly correlating
with surgical tissue specimen histopathology, which is the diagnostic gold standard. This pilot study
will first compare DSC-MRI measurements with tissue specimen histopathologic diagnosis of tumor
growth or post-treatment change to establish a set of threshold DSC-MRI values to distinguish the
two diagnoses. In addition, the DSC-MRI measurements will be compared with the amount of blood
vessels histopathologically identified from the same tissue specimens to provide further validation of
this technique.

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Mrinalini Kala, Ph.D.

St. Joseph’s Hospital
Award Amount FY09: $50,000

Role of B Cells In Glatiramer Acetate Mediated Suppression of Multiple Sclerosis
Multiple Sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS). The
CNS consists of the brain, spinal cord, and the optic nerves. Surrounding and protecting the nerve
fibers of the CNS is a fatty tissue called myelin, which helps nerve fibers conduct electrical impulses.
Myelin not only protects nerve fibers, but makes their job possible. Myelin is the target in an MS attack.
When myelin or the nerve fiber is destroyed or damaged, the ability of the nerves to conduct electrical
impulses to and from the brain is disrupted, and this produces the various symptoms of MS. In MS,
myelin can be lost in multiple areas, leaving scar tissue called sclerosis in the brain or spinal cord.
These damaged areas are also known as plaques or lesions. Sometimes the nerve fiber itself is damaged
or broken.
It has been estimated that MS is a leading cause of disability among young adults in North America
and Europe. Approximately 400,000 Americans have MS, and every week about 200 people are newly
diagnosed. World-wide, MS affects about 2.5 million people. Drugs recommended for its treatment
were designed to reduce autoimmune responses. Some of these therapies such as mitoxantrone,
corticosteroids and drugs in development like Fingolimod are based on generalized immunosuppression.
Other therapies including cytokine based strategies and monoclonal antibodies to various immune targets
are more selective in their effects. These treatments have improved risk to benefit ratios over generalized
immunosuppressant, but they are only partially effective and still have significant risks. All of these
therapeutic strategies are incapable of permanently stopping the immune attack on the CNS that
characterizes MS. The only immunotherapy for MS that is not based on immunosuppression is
Glatiramer Acetate (GA). GA (copolymer-1 or Copaxone) is a randomized copolymer that consists of
4 amino acids: L- alanine, L-lysine, L-glutamic acid and L-tyrosine. GA slows the progression of
disability as well as the relapse rate with few side effects. This makes GA a good candidate for our studies.
Our lab has shown that B lymphocytes have a role in suppression of MS by GA. In this proposal we
will examine how GA can modulate B lymphocytes and thereby affect the immune system. Our studies
will be carried out initially in the mouse model of MS and if they are successfu,l we will extend them
to humans. Understanding the mechanism of successful drug therapy will be a major advance towards
developing an effective therapy for Multiple Sclerosis.
Annual economic cost of MS in the United States is approximately $28 billion. In Arizona alone there
are at least 6000 people suffering from MS, and developing or improving a successful therapy will be
an immediate benefit for them and their families.

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Lei Lei, Ph.D.

Arizona State University
Award Amount FY09: $50,000
Function of Sox11 In Mammalian Cortical Development

The human brain has over 100 billion neurons and these neurons form specific connections. It is now
widely recognized that abnormal brain development during the critical periods such as prenatal, neonatal
and adolescent stages, underlies the etiologies of many mental disorders. According to the National
Institute of Mental Health, each year as many as 44 million Americans meet criteria for some mental
disorder, with roughly 12 million reporting symptoms so severe as to cause significant disability and
interference with everyday living. The economic cost of mental disorders are estimated at over $150
billion a year. Furthermore, mental disorders can also be fatal. Each year more Americans die from
suicide than from homicide. Like the rest of the nation, Arizona faces the ever-increasing challenge to
develop new diagnostics and therapeutics to treat patients with various mental disorders. However, in
order to accomplish this goal, it is imperative to understand the biological pathways and mechanisms
that control normal brain development and identify gene mutations and environmental factors that
cause mental disorders. In the past twenty years, although research using genetically engineered mice
has significantly improved our knowledge of development and behavioral neuroscience, we are just
beginning to have a comprehensive understanding of brain development and function. In order to reduce
the burden of mental and behavioral disorders, our government needs to continue to invest in
fundamental research in neuroscience.
Our long-term goal is to understand the molecular pathways and mechanisms that control brain
development. During fetal development, all of our neural cells are derived from a special type of cells
called neural progenitor cells. Neural progenitor cells divide and generate neurons, which then migrate
to occupy appropriate positions in the brain and form the correct connections with other neurons.
Abnormal generation or migration of neurons leads to dysfunction of the brain. In adult brains new
neurons are continuously generated in specific brain regions by neural progenitor cells albeit at a much
reduced level. Like other organs in our body, the development of brain is largely controlled by transcription
factors, which are proteins that serve as “switches” to tell cells what to do or what to become. Our central
hypothesis is that the transcription factor Sox11 controls neural progenitor cell proliferation and neuronal
migration during fetal development and in adult brains. Our objectives are 1) to determine the function
of Sox11 in regulating neural progenitor proliferation and 2) to determine the function of Sox11 in
regulating neuronal migration. In order to demonstrate the function of Sox11 in brain development, we
will use genetically engineered mice in which Sox11 is removed from specific nerve cells. Because mice
and humans share similar biological processes and developmental pathways, our studies using mice will
translate into a better understanding of human brain development. Moreover, our genetically engineered
mice may serve as animal models for understanding the causes of mental disorders. We anticipate that
the experiments proposed here will not only provide significant new insights into the specific mechanisms
of brain development, but may also lead to the identification of novel therapeutic targets for combating
developmental and neurological disorders including Schizophrenia, depression, and mood disorders.

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Kathryn Lemery-Chalfant, Ph.D.

Arizona State University
Award Amount FY09: $47,438

Molecular and Quantitative Genetic Approaches to Understanding Child Psychopathology
The Arizona Biosciences Roadmap emphasizes the need to strengthen the medical research base and
build a critical mass of firms and jobs with increased collaboration among higher education, nonprofits,
and industry. This project outlines an innovative interdisciplinary collaboration between Arizona State
University and the Translational Genomics Research Institute. Specifically, we aim to elucidate the
role of specific functional genes in child psychopathology (i.e., anxiety, depression, conduct disorder,
and attention-deficit hyperactivity disorder). The need to understand genetic influences on mental
health is underscored by findings that 10-15% of children exhibit clinical or subclinical disorders, and
most adult disorders have roots in childhood.
Mental disorders are the leading cause of disability in the US and Canada (World Health Organization,
2004), costing the US economy an estimated $105 billion dollars each year in lost productivity (National
Mental Health Association, 2001). Arizona currently ranks 18th in the country for employee poor mental
health days and 33rd in the country for overall health (United Health Foundation, 2007), so
psychopathology is a central issue to Arizona citizens and the Arizona economy. Investing in children
is an excellent way to ensure that overall health increases and the drain on the economy decreases in
the future. Lastly, effective pharmacological and behavioral prevention and intervention efforts require
an understanding of the role of genes and gene-environment interplay in child psychopathology.
We propose a molecular genetic study of child psychopathology. The participants are twin children
(many of whom have diagnoses of anxiety, depression, conduct disorder or attention-deficit hyperactivity
disorder), other biological siblings and biological mothers and fathers. These families have already been
extensively assessed with clinical interviews, hormonal measures, and observational assessment of
behavior and the home environment. In general, we believe that the identified candidate genes will
convey general risk for greater that one disorder and be associated with intermediate biological and
behavioral factors. For example, we hypothesize that genes that influence levels of the neurotransmitter
serotonin in the brain will increase risk for anxiety and depression through their influence on child
temperament, auditory and tactile sensitivities, and stress hormone levels. Further, we hypothesize that
the role of these genes on child psychopathology will depend on the family environment such as low
social class, negative parenting practices, and stressful life events. Genes are turned on and off depending
on the context, so models that allow for gene-environment interplay best represent reality.

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Lonnie Lybarger, Ph.D.

University of Arizona
Award Amount FY09: $50,000

Regulation of Immune Activation By Ubiquitination
The immune system is critical for the control of both infectious agents and cancers. However, this
powerful system also holds the potential for unwanted reactions against normal, “self ” targets (tissues).
Such untoward immune reactions are referred to as autoimmune reactions. Unfortunately, as a whole,
the frequency of autoimmune diseases has increased sharply in recent years. This includes diseases such
as asthma, arthritis, and food allergies, to name a few. In Arizona, the incidence of asthma exceeds the
national average and is on the increase. Further, with our aging population, diseases like arthritis are
particularly relevant. Clearly, this trend is alarming and represents a serious concern. The number of
individuals that are affected by autoimmune disorders is expected to continue to increase in the coming
decades and represent and ever-larger health system burden. Therefore, it is imperative to understand
the mechanisms that contribute to the generation of autoimmunity.
A general feature of autoimmune disease is uncontrolled activation (or priming) of the immune system
against self tissues. Normally, several “checks-and-balances” exist to prevent such aberrant activation,
many of which have been characterized in detail. Nonetheless, there is much that remains to be learned
about the cellular pathways that regulate activation. Indeed, a protein called MARCH1 was recently
identified that appears to play an unexpected role in controlling the initiation of immune responses.
MARCH1 is expressed in a subset of immune cells called antigen presenting cells (APC). APC are
critical for immune priming; they have the unique capability to activate T-cells. In APC, MARCH1
seems to diminish the ability of APC to activate T-cells by causing the selective destruction of other
proteins within the cell that are necessary for T-cell activation. Thus, MARCH1 is positioned to play
a substantial role in the control of immune priming. In spite of this, little is known regarding the molecular
details of MARCH1 function. We will explore this critical area and characterize the cellular pathways
utilized by MARCH1 to regulate the immune response. In turn, this knowledge will likely prove useful
for the future development of strategies designed to treat immune disorders such as autoimmunity.
Our lab has a longstanding interest in quality control pathways within cells. Such pathways are essential
to all cells and can remove unwanted or defective proteins. MARCH1 employs such pathways to cause
the destruction of other cellular proteins in APC that are required for immune activation, though the
details of the mechanisms employed by MARCH1 to accomplish this feat are poorly understood. We
have applied many of the techniques and reagents already available in the lab to the study of MARCH1
and have generated exciting preliminary data regarding the pathways involved in MARCH1 function.
We will extend our finding and test the hypothesis that MARCH1 invokes ubiquitin-dependent cellular
pathways to negatively regulate APC function. We will focus our analysis on a known target molecule
of MARCH1 called CD86, an essential protein for T-cell activation. Using a variety of cell biological
techniques, we will define the pathways employed by MARCH1 to target CD86 for destruction. In
addition, we will determine the role of these pathways in immune priming by APC. This project

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represents an essential step toward understanding the means by which MARCH1 is able to affect
immune priming, and it is fully anticipated that this knowledge will ultimately inform future studies
designed to alter priming for therapeutic benefit.

Anjan Misra, Ph.D.

St. Joseph’s Hospital
Award Amount FY09: $50,000

Exploiting Receptor Tyrosine Phosphatases for Diagnosis and Treatment
of Malignant Astrocytoma
Malignant astrocytoma are lethal brain tumors accounting for more than 50% of all brain tumors.
Survival has not changed in 3 decades despite most aggressive therapy. These tumors come in two grades,
Anaplastic Astrocytoma (AA, grade 3) and Glioblastoma Multiforme (GBM, grade 4). GBM has a
median survival of about one year and AA, about 3.5 years. Protein Tyrosine Phosphatase Receptor D
(PTPRD) is lost in AA and GBM (41-80% and 65-88%, respectively) and is associated with poor survival
in GBM (n=195). This suggests that loss of this protein helps malignant astrocytoma tumors. Other
groups reported that PTPRD is lost infrequently in other cancers (e.g., neuroblastoma, esophageal,
stomach and lung cancer). This makes PTPRD an ideal target for diagnostic and therapeutic use in
many cancer types, but specially in malignant brain tumors with protest outcome.
We hypothesize that PTPRD is a candidate tumor suppressor gene and loss of it helps tumor initiation
and/or progression maintenance of malignant astrocytic tumors.
The goals and objectives of this project are to investigate a) how frequently PRPRD is lost in malignant
brain tumors at protein level (as expected from preliminary data), b) whether higher grade malignant
brain tumors have a higher frequency loss than the lower grade tumors, c) how loss of this protein
affect tumor initiation, progression and behavior, and response to therapy, d) what are the normal
mechanisms of PTPRD loss in human brain tumors, and e) what are the pathways that are modulated
by this loss so that an intervention can be directed either directly to PTPRD or to pathway(s) it
influences. This information will help us strategize diagnostic and therapeutic applications of PTPRD
loss.

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Jong M. Rho, M.D.

St. Joseph’s Hospital
Award Amount FY09: $49,819
Epilepsy - Induced Impairment of Circadian Rhythms

Epilepsy is common neurological disease and afflicts 1-2% of the general population. The highest
incidence of epilepsy occurs in very young children and elderly adults. It is well known that epileptic
seizures can occur more commonly during sleep, and there is growing evidence indicating that many,
if not most, epileptic patients experience significant sleep problems. Since virtually all epileptic patients
are treated with anticonvulsant medications, it is unclear whether such sleep disturbances result from
the condition itself or as a consequence of chronic treatment with drugs. Sleep problems are often linked
to abnormal circadian rhythms (i.e., dysfunctional day-night cycling), and it is well known that the
brain’s internal master clock responsible for regulating these rhythms resides in the suprachiasmatic
nucleus (SCN) which is part of the hypothalamus. The major goal of this project is to evaluate circadian
rhythm disturbances in an animal model of early-onset epilepsy ( the epileptic Kcna1-null mutant mouse)
and to determine the cellular and molecular basis for this dysfunction by focusing on associated changes
in the SCN. There is growing evidence that SCN integrity is paramount to general health, and its
importance is underscored by the SCN’s role in regulating seizure activity, contributing to sleep
disorders, obesity and overall neuropsychological functioning. Given the epidemic of sleep problems
and obesity currently faced by the general population in Arizona and throughout the United States,
the results of the proposed studies may help expand our knowledge regarding SCN function to a wide
range of physiological and neuroendocrine functions.
The principal goal of the project is to determine whether there are intrinsic functional abnormalities
of the suprachiasmatic nucleus (SCN) of epileptic knockout mice and to identify the gene(s) responsible
for abnormal circadian function. This research study comprises three specific aims. In the first aim,
we will determine whether impairment of normal circadian rhythms in our mouse model is associated
with the post-natal development of epilepsy. We hypothesize that circadian rhythm expression and phase
shifts are altered after onset of spontaneous seizures in Kcna1-null epileptic mutant mice, and that prior
to the onset of spontaneous seizures, circadian rhythm expression does not differ between Kcna1-null
mutant and wild-type mice. In the second specific aim, we will examine the circadian firing patterns
of SCN neurons in organotypic slice cultures prepared from Kcna1-null mutant mice using multielectrode array recordings. We hypothesize that circadian firing patterns of SCN neurons form Kcna1null mutant mice are either phase-shifted, or are irregular or shortened, compared to those of wild-type
mice.We further predict that prior to the age of seizure onset, circadian firing patterns of SCN neurons
from Kcna1-null mutant mice will resemble those of wild-type mice. Finally, in the third specific aim,
we will determine whether circadian rhythm abnormalities in epileptic Kcna1-null mice are associated
with differential expression of clock gene protein products. We hypothesize that SCN neurons will
express abnormal circadian expression patterns of clock genes (e.g., Per1, Per2, and BMAL) in Kcna1null mutant mice, and that prior to the onset of spontaneous recurrent seizures, circadian expression
patterns of these clock genes in Kcna1-null mutant mice will resemble those of wild-type control mice.

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Overall, we hope to demonstrate that there are intrinsic abnormalities of clock gene expression, SCN
firing patterns and circadian phase shifts in epileptic mice, and that these finding occur after the onset
of the epileptic state.

Leslie S. Ritter, Ph.D.

University of Arizona
Award Amount FY09: $47,608

Novel Use of a Natural Product for Acute Stroke Therapy
Stroke is one of the leading causes of death and disability in the United States and in Arizona. However,
there is currently only one approved treatment, a clot-busting drug, to protect brain cells from death
during the time of a stroke. Other drugs have all failed for several reasons. First, the experimental
drugs that were tested were not well-characterized, or treated just one cause or pathway of brain cell
death. Second, the experimental models that were used did not fully represent the human stroke
condition. Our study is designed to overcome these problems. Natural products isolated from medicinal
plants have not previously been tested for stroke treatment but are attractive candidates for testing because
they are made up of multiple compounds that can act at multiple levels to prevent brain injury.
Turmeric, the natural product to be tested in this study, is well-characterized and is known to affect
multiple inflammatory pathways that injure the brain after stoke. Also, the experimental model of
stoke that will be used in this study is one that is recommended by national advisory panels. The
inflammatory pathways that injure the brain after stoke that we will study involve the white blood
cells (neutrophils) and the cells that line the blood vessels (endothelial cells). Dr. Ritter, the Principal
Investigator, was the first to discover that a tremendous amount of white blood cells stick to the blood
vessels of the brain after a stroke. When this occurs, the white blood cells release an overabundance of
toxic substances which damage the blood vessels and the brain tissue. Dr. Funk, the Co-Investigator,
was the first to discover that a well-characterized turmeric dramatically reduced severe joint damage
in rheumatoid arthritis by blocking the damaging effects of the white blood cells. These collaborating
investigators asked the question, “Would this natural product also block the damaging effects of the
white blood cell after stroke?” Our project has been designed to answer this important question.
The major hypothesis to be tested is that a well-characterized natural product, turmeric, will reduce
brain damage after stroke, and it will do so by affecting multiple inflammatory pathways that involve
white blood cells (neutrophils) and blood vessels (endothelial cells).The specific objectives of our study
are 1) to determine the ability of a well-characterized turmeric extract to prevent brain injury in a animal

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model of stroke that is relevant to the human condition, 2) to assess the ability of turmeric to block
neutrophil adhesion to the blood vessel endothelial cells, an event that is a major contributor to brain
injury after stroke, and 3) to identify inflammatory signaling pathways at the neutrophil/endothelial
interface that are targeted and blocked by turmeric.
As strokes are the third leading cause of death and major cause of disability, identification of a safe
and beneficial effect of turmeric that could act in a novel way to limit brain injury in stroke could
have a major impact on the health and health care costs of the state of Arizona. This is particularly
true at a time when baby boomers approach retirement and the percentage of our population over the
age of 65, i.e. those individuals at greatest risk of stroke, is projected to double. Strong public interest
in botanical supplement use is clearly supported by recent national health surveys (CDC). This project
will also provide opportunities for the Arizona Board of Regents to be at the forefront of a new business
model that will allow for the development and commercialization of complex natural products for stroke
using a pharmaceutical approach.

Marek Romanowski, Ph.D.

University of Arizona
Award Amount FY09: $50,000
Contrast Agent for Colonoscopy

Despite the steady decline of its incidence rate, colorectal cancer remains the third most common
cancer and the third leading cause of cancer death, killing one in seventeen men and one in nineteen
women in the United States. Most carcinomas of the colon develop from preexisting polyps. Medical
practice clearly demonstrates the importance of screening followed by resection of polyps, or polypectomy,
and among currently recommended screening methods, colonoscopy is considered the most sensitive.
Following polypectomy the incidence of colorectal cancers has been shown to fall by half or even more.
However, small or difficult to identify polyps could have been missed only to progress to invasive
cancer in the remaining half of patients.
Approximately 2750 Arizonans will be diagnosed with cancer of the colon or rectum in 2007 and 970
will die of this disease. The incidence rate of colorectal cancer dramatically increases with age. The
U.S. Census Bureau projections indicate that between the years 2000 and 2030 the elderly population
of Arizona will more than triple, an exceptional growth rate projected in only two other, less populous,

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states. This evolving demographic will require accelerated development of highly effective and accessible
methods of preventive screening.
The overall goal of this project is to develop a contrast agent that would enhance existing diagnostic
techniques by marking areas of precancerous changes, or adenomas, with highly visible luminescent
dyes. The proposed contrast agent will employ upconverting nanoparticles. This class of optical materials
has only recently been contemplated for biomedical use, and its diagnostic application discussed here
is new and unique. The safety, chemical stability, and high contrast associated with upconverting
nanoparticles are superior to many standard molecular probes or quantum dots. These silica-encapsulated
particles have no discernable color under ambient light. However, when exposed to invisible infrared
illumination, they emit bright colors. Targeting precancerous changes will be possible by including in
this design highly selective and robust molecules capable of recognizing early markers of disease. When
fully developed, the proposed contrast agent will provide functional enhancement of colonoscopy and
other endoscopic techniques. One of the more exciting possibilities is its use in conjunction with the
wireless endoscopic capsule technology recently approved by FDA for examination of esophagus and
small intestine and currently in development for imaging of the entire gastrointestinal track. At the
successful completion of this project we will seek funding from federal and commercial sources, which
would allow for continuing research as part of the colon cancer prevention programs at the Arizona
Cancer Center.

Jiong Shi, M.D.,Ph.D.

St. Joseph’s Hospital
Award Amount FY09: $50,000

APOE Mimic Peptide as a Novel Therapy on Cognition in a Transgenic Mouse Model
Multiple sclerosis (MS) is a devastating disease that causes not only motor deficits but cognitive ones
as well. MS is a leading cause of disability in young adults, with most people experiencing their first
symptom between the ages of 20 and 40. Cognitive symptoms of MS are considered the most debilitating
and have the heaviest impact economically and socially. Studies indicate and our research confirms
that 40-70% of patients with multiple sclerosis (MS) exhibit significant cognitive impairment. Our
studies found a strong association between the development of cognitive problems and a gene for
apolipoprotein E4 (APOE4). Our studies further indicated that a markedly disproportionate percentage
of the young patients with cognitive deficits have the APOE4 gene. Apolipoproteins are lipid-binding
proteins which are necessary to promote repair of injured neurons, cells of the brain. APOE 4, however,

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is less efficient and more likely to be cleaved by enzymes than the other types. Understanding the role
of APOE in MS and how the different types of APOE interact with the disease to affect cognition is
our goal. Animal models provide the best methods of determining the mechanisms. Experimental
autoimmune encephalomyelitis (EAE) is the best studies animal model for MS. Mouse models allow
us to use genetically altered (transgenic) mice which have or do not have the gene of interest.
We will use transgenic mice which have no APOE (APOE knockout) and to have APOE 4 (APOE 4
knock-in) and compare their cognitive function to mice with normal APOE after inducing them with
EAE, the animal version of MS. We will test them early in the course of the disease, as our MS studies
indicate that cognitive symptoms precede motor and may be the first indication of disease.
We will test their cognitive function using a water maze and examine their brain using special stains
for chemical and cellular changes seen in the hippocampus, the memory region of the brain. We will
also look for electrophysiologic changes using a wll0-studied synaptic model for memory.
Finally, we will use APOE peptide mimetic, a peptide–small protein fragment–which mimics the
therapeutic effect of APOE to determine if it can overcome the detrimental effects of the absent
(knockout) and less efficient APOE 4.
Understanding the role of APOE on the MS mouse model will provide us with valuable insight
regarding the mechanisms of the cognitive decline in the susceptible MS population. Identification of
cognitive symptoms prior to the onset of motor symptoms in the animal model of MS and determination
of the role of APOE at this early stage should result in clinical trials designed to identify the disease
in the earliest stages enlarging the therapeutic window in which the disease can be addressed and
potentially reversed. Determining the mechanism and efficacy of competitive inhibition using APOE
mimetic peptides will provide further insight, promote the rapid translation to human trials, and
promote further investigations into competitive inhibitory therapies for this devastating disease.

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Catharine L. Smith, Ph.D.

University of Arizona
Award Amount FY09: $49,999

Identification of the Acetylated Transcriptional Proteome in Leukemia
Cancer is the leading cause of death in Arizona children under the age of 15 and leukemia and
lymphoma are the first and third most prevalent childhood cancers in the state (American Cancer
Society, Arizona Cancer Facts and Figures, 2004-2005). In addition, the incidence of these cancers
increases with age; in adults, these cancers are most prevalent after the age of 60 (Leukemia and
Lymphoma Society, http://www.leukemia-lymphoma.org/). Given its sizable community of retired
adults, its is not surprising that leukemia and lymphoma rank among the top 10 causes of cancer death
in Arizona as of 2004. A new class of anticancer drugs, histone deacetylase (HDAC) inhibitors, has
shown promise in treating these cancers. These drugs inhibit enzymes that remove acetyl groups from
proteins. The presence of these groups can modulate the activity of proteins thus protein acetylation
is considered an important regulator of cell function. HDAC inhibitors can induce either a halt to
growth of the death of cancer cells by mechanisms thought to involve changes in gene expression.
Although they are sometimes effective in leukemia/lymphoma patients, it is difficult to predict who
will benefit from these drugs. This is partly due to the lack of identified acetylated proteins known to
be important for regulation of leukemia/lymphoma cell growth. Detection of such proteins in cancer
cells could serve as an important predictive tool. In addition, cancers are most often treated with
multiple drugs and it is unclear which drugs would work best in combination with HDCA inhibitors
to increase both the number of patients who might benefit from these drugs and the rate of patient
survival.
The hypothesis of this project is that genes rapidly regulated by the inhibition of HDAC activity will
be bound and coregulated by proteins which are acetylated and thus targeted by HDACs. Proteins
bind to genes by recognition of specific DNA sequences. We propose that computer-aided analysis of
such sequences in the genes regulated by HDAC inhibitors will reveal the enrichment of binding sites
for proteins potentially regulated by acetylation. The acetylation status of such proteins will be assessed
using new and powerful mass spectrometry methods. The project has three aims. First, we will identify
the genes commonly regulated by HDAC inhibitors in five leukemia/lymphoma cell lines that are
likely to contribute to regulation of cell growth and survival. Second, we will analyze these genes for
the presence of common binding sites for gene regulatory proteins. Third, we will determine which
gene regulatory proteins are acetylated in response to drug treatment in leukemia and lymphoma cells.
The overall objective of the proposed study is to identify acetylated proteins critical for mediating the
death of leukemia and lymphoma cells through regulation of gene expression.
This study will address a major gap in our understanding of acetylated gene regulatory proteins
important for controlling growth and survival in leukemia and lymphoma. These proteins are likely
to be the mediators of drug action and the resulting halt of cancer cell growth. The acetylation status
of these proteins could serve as potential diagnostic tools to determine whether individual patients would

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benefit from treatment with HDAC inhibitors. The identity of these proteins could also provide insight
into which other drugs might be used in combination with HDAC inhibitors to increase their efficacy
and boost the rate of disease-free survival. The unique integrated approach we propose could also be
applied to other cancers in which HDAC inhibitors show effectiveness and to other anti-cancer drugs
which work through changes in protein modification.

Peter N. Steinmetz, Ph.D., M.D.

Arizona State University
Award Amount FY09: $48,744

Representation of Memory for Spoken Words and Voice Detail by Single Neurons
in the Human Hippocampus
The problems posed by illnesses affecting memory, such as Alzheimer’s disease, assume increased
importance as people live longer on average, creating a growing population that is susceptible. An
inability to remember names, statements and instructions can be particularly debilitating. Understanding
how such linguistic memories are stored in the brain is a key step toward developing better therapies,
but this is difficult to study in non-human animal models of disease because spoken abstract language
is not present. Although non-invasive measurements, like brain imaging and scalp electrical activity
monitoring, provide information about average activity in the human brain, these techniques lack the
ability to describe exactly which cells in different brain areas are involved on the time-scale of single
cell activity, which is the fundamental unit of information representation in the brain.
This project overcomes these limitations by measuring the activity of single neurons in the human brain
under extraordinary circumstances - when epilepsy patients require implantation of electrodes for
clinical monitoring. While the patients are implanted with electrodes, they can volunteer to perform
experiments where they are asked to remember spoken words and later recall them. By measuring the
activity of single neurons near the tip of the electrodes and correlating this activity with the patient’s
recollections, we can determine which brain areas and connections, or circuits, between brain cells are
critical to correct recollection.

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Since memory of spoken language has never been studied in two brain areas where the electrodes are
placed (hippocampus and amygdala), our initial goals are to determine how memory for spoken words
in a simple task is represented in these brain areas. The task performed by the subjects is simply to
remember whether they have heard the word before or during the experiment. The spoken words are
played through headphones with different amounts of delay between their first and second presentation,
and also spoken half the time in a different voice. Our hypothesis is that both the amount of delay
between presentations and whether the same or different voice is used will change the responses of
single neurons in the human hippocampus and amygdala. This is based on the observation that both
of these variables, delay and voice, affect the ability of normal subjects to accurately recall whether
they have heard the word before, as well as many other observations showing that the hippocampus
is involved in the recollection of events and facts.
To test this hypothesis, we record the activity of single brain cells near the tips of the implanted
electrodes as the patients perform this task. The average activity, or rate of firing, will then be correlated
with both the delay and voice, as well as how well the patients recall hearing the words.
The results of these experiments will provide a basic groundwork for understanding how memory for
spoken language is represented in these brain areas, facilitating further work examining memory for
more complex and abstract linguistic structures such as sentences. These results will also expand our
ability to target new therapies for memory disorders to particular cell types and brain areas. The
demographics of the state of Arizona make improving these therapies a particularly important issue,
since failures of memory (dementias) occur more frequently in the elderly.

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Raoul Tibes, MD, Ph.D.

TGEN
Award Amount FY09: $50,000

RNAi Kinome Screening to Identify Rational Combinations with Cytarabine
in Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is the most common adult acute leukemia and one of the deadliest
cancers. In fact, leukemias are the 5th and 6th leading cause of cancer deaths in men and women,
respectively, and AML is responsible for the majority of these deaths. Overall only 5-10% of AML
patients are alive at 2 years. Unlike other leukemias and cancers, AML therapy has not much improved
over the last decades. Therefore, new therapies are urgently needed to treat patients with AML.
Cytarabine (a “chemotherapy”) is the most active drug used in AML and can cure a small fraction of
AML patients. However, many patients are resistant to Cytarabine based therapies, leading to inadequate
treatment of their AML. It is not yet understood which are the genes that lead to Cytarabine resistance.
Identifications of these genes would increase our understanding and guide the development of new
and better therapies to treat AML with Cytarabine based therapies.
Many of the genes that are involved in leukemia development and resistance are kinases, a group of
enzymes that drive growth of leukemia cells. In the past researchers were only able to analyze one or
a few single genes/kinases that they thought might have a role in Cytarabine resistance. This is because
the technologies have not been available to test hundreds of kinases at the same time to see if they can
slow down growth of leukemia cells. A new discovery that was awarded the Nobel Prize for Medicine
now makes it possible to use short stretches of RNA (base pairs similar to the DNA in cells) that can
be brought into cells and very selectively reduce the activity of individual genes. Now hundreds of genes
and kinases can be studied at the same time to identify which individual kinase plays a role in conferring
resistance to Cytarabine in AML. Discovery of these genes can be utilized to develop new therapies to
improve response to Cytarabine based therapy and ultimately increase survival for patients with AML.
We hypothesize that certain, yet unknown kinase genes have a function to make AML cells resistant
to Cytarabine. This research proposes to inhibit the function of several hundred kinases to test if
inhibiting the function of one of those genes can reverse the resistance to Cytarabine. We will take
Cytarabine resistant leukemia cells and incubate them with Cytarabine and short RNA pieces that inhibit
the function of a single gene (knock down). Consequently, if a gene produces Cytarabine resistance,
inhibiting its function would increase leukemia cell death. This implies that cells have regained their
sensitivity to Cytarabine. We will do this for ~600 genes, the so-called kinases. The genes that help
make cells the most sensitive to Cytarabine will be tested further. This validation step is important to
increase our confidence that those kinases are indeed the most important ones. In additional experiments,
we will then look at the mechanisms of what happens to the proteins of those genes and assess the
activity of those proteins.
The approach in this project will help to find the important kinase genes that confer resistance to

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Cytarabine in AML. Once those genes have been identified, new drugs and therapies can be developed
against those genes/kinases and be combined with Cytrarabine to improve treatments for patients with
AML.
This project is important for Arizona because it contributes to a new program that has started to
improve leukemia treatment, care and research in Arizona. This project leverages the clinical expertise
of the applicant with the knowledge and resources at the institution where the research will be conducted.
The facility for the short RNA stretches to reduce the function of genes is one of the few highthroughput in a not-for profit research institute in the nation. There is a unique opportunity for this
project to be successful and to attract attention to Arizona as a new developing biomedical center.
Furthermore, the results generated from this project will help develop new projects and allow investigators
to apply for national grant funding increasing the competitiveness of Arizona in research and
biotechnology. With promising new findings, new drugs can be developed here in Arizona involving
new and start-up biotech companies.

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Theodore Trouard, Ph.D.

University of Arizona
Award Amount FY09: $50,000

MRI, MRS and Molecular Modeling of Three Dimensional Cell Cultures
Diffusion-weighted MRI(DWMRI) is a technique that allows non-invasive measurements of the
microscopic motion of water in living tissue. Because the motion of water is sensitive to the local
cellular environment, DWMRI is being used to study a variety of diseases including stroke and cancer.
Within minutes after a stroke has occurred, the area of brain tissue affected by the stroke shows up
very bright on a DWMRI image compared to normal brain tissue, which allows physicians to
unambiguously identify the tissue involved in the stroke. More recently, DWMRI has also been used
to monitor the early effects of chemotherapies in cancer. It has been shown that the motion of water
in tumors changes in response to successful therapy and that this change occurs prior to any measurable
change in the size of the tumor. Although these observations in stroke and cancer are clinically useful,
the underlying reason for the changes in water diffusion is still unknown. The more we know about
how water moves within tissue, the better we will be able to interpret results from the numerous
DWMRI exams being carried out in stoke and cancer and the better we will be able to treat these
diseases.
The goal of this project is to better understand why the motion of water, as measured by DWMRI,
changes after stroke and successful cancer therapy. To begin to reach this goal, we will carry out MRI
experiments on unique cell culture systems developed at the University of Arizona to study the motion
of water in well defined and easily controlled environments. These experiments will allow us to make
detailed measurements of water movement in normal cells, swelled cells, shrunken cells and ischemic
(stroked) cells. We will also develop realistic mathematical models with which to describe water motion
in simple cell systems and predict the results of DWMRI experiments. The mathematical models will
allow us to determine which biophysical properties are important to water diffusion and which are
responsible for the changes observed in stroke and cancer therapy.

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Pak Kin Wong, Ph.D.

University of Arizona
Award Amount FY09: $49,999

Molecular Probe Biosensors for Rapid Screening of Photoprotective Compounds
Currently, Arizona has among the highest incidence rate of skin cancer in the world, so we are interested
in agents that can suppress solar damage relevant to skin cancer. Our team, in collaboration with the
Department of Pharmacology and Toxicology, are currently investigating natural and synthetic compounds
to serve as prototype photprotective agents. In order to perform a large-scale screening of photoprotective
compounds, we plan to develop an automated platform for high-throughput screening of chemopreventive
agents. The technological core of the rapid screening system is two molecular biosensors for rapid
detection of the cellular antioxidant response. In addition, a microfluidic platform will be developed
to facilitate large-scale screening as the microfluidic system automates a large number of measurements
simultaneously and the amount of reagents required is dramatically reduced.
The overall goal of the project is to develop a rapid screening system for identifying chemopreventive
compounds. Chemopreventive compounds often exert their effects by inducing the expression of
cytoprotective enzymes to defend cells from oxidant stress and reactive carcinogenic intermediates.
The expression of many cytoprotective enzymes is regulated by the NF-E2-related factor 2 via antioxidantresponsive elements. Here, we plan to develop two molecular probe designs and a microfluidic platform
for rapid detection of the ARE-bound Nrf2 protein and Nrf2-mediated gene expression for identifying
potential chemopreventive compounds. The molecular biosensors will form the technological core of
a high-throughput screening system. To evaluate the assays, human skin cells are chosen as cell-based
model. The development will lead to a rapid, quantitative, sensitive, and specific screening system for
rapid identification of chemopreventive compounds. The system will provide an alternative for reducing
animal usage in predicting the effects of chemopreventive compounds and elucidating their mechanisms
of action. The assays should also be generally applicable to a wide range of toxicology studies, as they
are compatible with various in vitro models.

103

104

Section E
Indices

105

106

Principle Investigator Index
Adler
Akporiaye
Aspinwall
Azhar
Barnard
Beyer
Boyer
Bremner
Bunch
Buneo
Caplan
Chambers
Chang
Chen
Coast
Coleman
Conde (Martinez-Conde)
Conrad
Coon
DiBaise
DiStefano
Dixon
Dougherty
Duggan
Dvorak
Ewell
Falk
Fares
Gaballa
Garewal
Ghosh
Gillies
Gmitro
Goldman
Gunatilaka
Halpern
Hammer
Hildenbrand
Hsieh
Hu
Hurley
Kala

Keim
Kiela
Lane
Lei
Lemery-Chalfant
Lewis, E.
Lewis, J.
Li
Lopez
Lybarger
Macknick
Mandarino
Martinez
Martinez-Conde (Conde)
Misra
Molnar
Muthuswamy
Nagle
Panitch
Pettit
Posner
Preul
Rance
Rho
Ritter
Rogers
Romagnolo
Romanowski
Rose
Scheck
Schluter
Schroeder
Selmin
Service
Shi
Skibo
Smith
Sparks
Steinmetz
Sun
Tibes
Tillery

3
53
29
71
29
54
6
72
7
55
74
55
30
75
31
31
60
76
77
32
8
32
33
9
10
34
79
80
11
56
81
35
12
82
13, 57
58
58
37
84
86
14, 15
87

107

59
59
38
88
89
16
17
17
39
18, 90
40
40
41
60
91
19
20
42
43
62
62
43
44
92
93
21
63
94
44
23
45
64
65
45
24, 95
46
97
65
98
25
100
83

Treiman
Trouard
Tsang
Tsao
Vernon
Witte
Wondrak
Wong
Wu
Yang
Zarnescu
Zohar

46
102
25
47
66
48
49
103
26
66
67
50

108

Subject Index
Aβ
adiponectin oligomerization
aging
AKT (protein kinase B)

21
47
45
59
81
3, 54
17, 21, 31, 65
8
29
57
71
66
95
9
45
45
45, 87, 90

aPKCζ
α-synuclein
Alzheimer’s disease
American Indians
angiogenesis
Annexin II
aortic aneurysm
AP-1 inhibition
apolipoprotein E4
Auricular-condylar Syndrome
arthritis, rheumatoid
autoantibodies
autoimmune disease

B cell
BACE1
Barrett’s esophagus
Basal Ganglia
basement membrane
Bcl-2 gene
Bcl-2 promoter
beauvericin
BDNF
17β-estradiol
bile acids
biomarker
biosensor
BRCA-1 gene

45
17
10
83
74
16
15, 16
13
3
17
10, 41, 58
3, 56
103
63

c-fms gene
cancer
astrocytoma
bladder
breast
colorectal
esophageal
glioma

109

55
91
33
39, 55, 63, 64
41, 56, 94
10
34, 86

leukemia
lung
melanoma
meningioma
pancreatic
prostate
skin
c-Fos Phosphorylation
c-MYC promoter
CD44
Chagas’ Disease
chemical labels, biomimetic
chromosome 3q
chromosome 20
cinnamic aldehyde
circadian rhythms
Coccidioides Posadasii
cognitive performance
copper
cortical development
COX-2 inhibitor
curcumin
cyclooxygenase-2 (COX-2) inhibitors
cyclooxygenase-2 (COX-2) promoters
Cytochrome c Oxidase I (CcOI)
dendritic cells
depression
deoxycholic acid
diabetes
diabetic kidney disease
diagnostic
DJ-1 protein
dopamine
Drospohilia
drugs
anticancer
cell motility inhibitor
eIF3f gene
embolization
embryonic stem cell regulation
endocytosis
endogenous MAZ

14, 97, 100
72, 77
24, 49
23
35, 57
42, 62
32, 103
75
14, 15
64
37
29
8
9
49
92
59
65, 95
65
88
59
77
63
56
53
38
41
40, 47
8
31
3
58
7, 45, 67
19, 44, 66, 97
13
24
66
81
80
14

110

endoscope, ultra miniature
epilepsy
erythromycin
estrogen
exercises

12
40, 46, 92
32
44, 76
31

febrile seizures
fibroblast patch
folate
Fragile-X syndrome

46
82
65
67

G-quadruplex
GABAc receptor
gastric acids
gastroparesis
GGA repeat region
glutamate
glycoursodeoxycholic acid

14, 15
30
10
32
14
58
10

hairless protein, mammalian
HDAC Inhibitors
heart rate variability (HRV)
histone deacetylase (HDAC) inhibitors
hnRNP K
human umbilical cord blood cells (hUCBCs)
HuR protein
hyaluronic acid gel

84
97
38
97
24
11
55
43

ictal blood flow
lkB protein
IL10
i-motif
imaging
imaging probe
immunotherapy
IMP Dehydrogenase
inflammation
inflammatory bowel disease

40
40
45
15, 25,
6, 35
29
25
46
40
59

kidney disease
kissing bug

8
37

Laminin-332
ligands

42
25, 35

111

lymphedema

48

Macrophage Activating Factor (MAF)
mammography
MARCH1
massage therapy
MAZ
memory
MEMS microflex interconnect (MMFI)
mental retardation
metabolic syndrome
metastasis
MHC class I molecules
microelectrode
microsaccade
motor learning
motility, cell
MRI, diffusion weighted
MRI, dynamic susceptibility contrast
MR Spectroscopy
MUC1
Multiple Sclerosis
MYB gene
myocardial infarction

43
39
90
48
14
20, 98
20
67
40
42, 49, 64
18
20
60
83
13
34, 102
86
34, 102
87, 95
11, 82

nAChR
N-acetylated-alpha-linked
acidic dipeptidase-like-protein (NAALADL2)
necrosis
necrotizing enterocolitis (NEC)
neural sclerosis
neurodegeneration
neuroprosthetics
neurotoxicity
neutrophil function
NIPAAm -based copolymer

26
8
34
58
40
54
83
6
59
66

parietal area
Parkinson’s Disease
Parkinson’s Disease with Dementia
PEDF
photoprotective compounds
polysilicon interface
progressive supranuclear palsy

55
3, 54, 79
3
79
103
20
60

112

Protein Tyrosine Phosphatase Receptor D
psychopathology, child

91
89

Regional Tribal Institutional Review Board
replication-defective lentiviral (HIV) virus
respiratory muscles
retinal pigment epithelium (RPE)
rhizosphere of desert plants
RNAi Kinome

17
25
31
79
19
100

scaffolds, biomimetic
Schizophrenia
scorpion sting
scorpion neurotoxicity
signal transduction pathway
SM16
Sox11
spinal cord injury
spoken word
state estimation
stem cells
stroke
SUCNR1
sulfonium-salt
supranuclear palsy
syndrome, auriculo-condylar

43
58
6
6
62
53
88
43
98
55

T cell
TCR mAAbs
thermoregulation
TGF
TGF-β ligands
Triatoma rubida
Tribal community participation
trichloroethylene
Trypanosoma cruzi
tumeric
tumor cells, circulating
twins

45
45
44
53
71
37
17
65
37
93
50
89

ubiquitination
umbilical cord blood cells

90
11

93
8
44
60
9

vaccine technology

18, 53

113

vagal tone disregulation
valley fever
vasculogenesis
VEGF
VEGF gene
VEGF promotor
visual fixation

38
59
11
33
25
25
60

Withaferin A
Wnt signaling pathway

57
23

114