IIMS/CTSA NewsInstitute for Integration of Medicine & Science/Clinical & Translational Science Award A Partnership to Improve Health

Special 2011 Edition iims.uthscsa.edu

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Description of IIMS/CTSA awards

Pilot Projects - The primary goal of this program is to support early-stage collaborative translational and clinical studies that will lead to increased interdisciplinary, institutional, and community-based research likely to compete successfully for national grant support and ultimately to improve human health. The maximum budget for these one-year awards is $50,000. The RFA is normally issued in December with a Letter of Intent due in January and the completed grant due in February. Awards are typically made in May and funding runs from May 1 – April 30.

Translational Technology Resources (TTR) Supplements - The primary goal of this program is to provide additional funding for translational research projects requiring the use of technologies in shared resources. The proposed research must have relevance to clinical and/or translation science. Funding of a TTR supplement will specifically be used to offset the cost to the researcher of resource usage (in-full or cost-shared) and will be dispersed to the resource directly upon completion of services. The maximum budget for these one-year awards is $10,000. The RFA is normally issued in December with the completed grant due in February. Awards are typically made in May and funding runs from May 1 – April 30.

Mentored Research Career Development (KL2) Program - The Program focuses on the very best of the best junior faculty who are committed to a research career in clinical and translational science. Salary support is provided by the KL2 Program to provide protected time for research and training activities; limited research support as well as travel expenses are also provided. The program provides an intense, personalized research training and career development experience that optimizes chances for a successful research career as an independent investigator. Candidates selected for participation in the Mentored Research Career Development Program will be designated as KL2 Scholars. Application deadline for the KL2 program is December 1, with a start date of May 1.

Translational Science Training (TST) Across Disciplines - The goal of the Translational Science Training (TST) Program is to enhance the quality and scope of the doctoral research experience by offering additional interdisciplinary research training and mentorship in Translational Science. The TST Program is made possible through a grant from the University of Texas System Graduate Programs Initiative. Each year, up to six Translational Science Training Scholars will be selected on a competitive basis. Awards will include up to $26,000 annually in stipend, plus research and travel support. TST Scholars will be encouraged to access facilities, equipment, and other resources available through the Institute for Integration of Medicine and Science to support their translational research. Continuation in the program will be based on a semi-annual evaluation process. Applications are due May 1.

For additional information on each of these programs, visit our website: iims.uthscsa.edu

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Timothy Duong, PhD – Research Imaging Institute – 2 Pilot Projects, 3 TTR Awards

I am extremely grateful for the multiple IIMS/CTSA Pilot and TTR grant awards from the IIMS/CTSA over the past 3 years. The missions of our laboratory are to develop in-vivo MRI technologies for studying the brain and the retina, in animal models and humans. We focus on applying these imaging technologies to study ischemic stroke and retinal disease (retinal degeneration and diabetic retinopathy) in both animal models and humans. These IIMS/CTSA awards broadly supported all major aspects of our work and missions, and they have helped to move our research forward. Specifically, these awards have enabled and continue to enable in very substantial ways: i) the development and testing of novel ideas and projects working with our collaborators, ii) many publications, iii) the expansion of works on a few NIH-funded grants, iv) the successful competitive renewal of an NIH grant award, v) submission of three NIH grants, and vi) and the support of many pilot experiments carried out by our PhD and MD students and postdoctoral trainees who subsequently obtained their own training grants (such as IIMS TST, American Heart Association, and other grants).

Bin Zhang, MD, PhD – 1 Pilot Project, 3 TTR Awards

With the support of multiple IIMS/CTSA awards (1 pilot project and 3 TTR awards), Dr. Zhang has been focusing on a protein called CD73 on the surface of ovarian cancer cells, which seems to prevent immune cells including T cells, from attacking tumor cells. Thus, CD73 may serve as an emerging target for ovarian cancer treatment. In a mouse model of ovarian cancer, Dr. Zhang has used small molecule inhibitors and monoclonal antibodies to block CD73 and was able to improve T cells’ ability to fight the tumor. These results were published in high-impact journals such as Journal of Clinical Investigation and Cancer Research (cover feature). Moreover, He was recently funded by NCI R01 and Ovarian Cancer Research Foundation. His current research is to further elucidate how CD73 regulate anti-tumor T cell trafficking in the tumor microenvironment

using a variety of imaging approaches including intravital microscopy, Xenogen IVIS imaging system and MRI. The results obtained will continuously add considerable leverages for future high-impact publications and NIH grants. More importantly, Dr. Zhang hopes to translate this knowledge into new strategies for improving ovarian cancer immunotherapy.

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Patricia Dahia, MD, PhD – 2 Pilot Projects, 2 TTR Awards

Dr. Dahia first received funding from the GCRC in 2007 as part of the Clinical Research Feasibility Funds (CReFF) program and since 2009, she has received two pilot project awards and two Translational Technology

Research Supplements.

CreFF project This pilot project provided funds for generation of global expression profiling data of pheochromocytomas of distinct genetic origins. These studies led to the identification of subclusters of tumors with shared transcription features that were instrumental for later identification of novel genetic forms of pheochromocytoma (i.e, TMEM127-mutant tumors) and for defining subclusters associated with metabolic disruptions. These studies supported two successful grant applications: Kimmel Foundation Scholarship and a Voelcker Young Investigator Award.

Projects 1-3 have provided support for generation of data describing the identification of a novel tumor susceptibility gene, TMEM127, and its preliminary functional characterization (1).

Of more direct translational relevance, these funds also supported the initial data examining the clinical consequences of these mutations and the specific features of the novel syndrome caused by TMEM127 mutations as part of a large, multi-institutional effort (2). In addition, these pilot projects enabled the generation of additional preliminary data, including the development of a mouse model of conditional Tmem127 inactivation, along with other in vitro data, that supported 6 grant applications, of which 3 have been funded (CPRIT, Alex’s Lemonade and Concern Foundation) and 3 others are pending (listed below). In addition to publications and funding, other outcome measures that derived from these projects were invitations to speak at national and international conferences and to contribute a review article for a peer-reviewed journal.

Project 4 This project has just been selected for funding. With this pilot study we intend to further our studies that aim to discover novel susceptibility genes using new sequencing technology. We will continue to exploit hereditary tumors as a model system in these studies. The CTSA funds will be used for salary support of a postdoctoral fellow and initial exome sequence

of selected s a m p l e s from familial or high-risk cases (early onset or multiple t u m o r individuals).

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Ricardo Aguiar, MD, PhD – 1 Pilot Project, 2 TTR Awards

Our group is interested in developing novel rational therapeutic strategies for the treatment of B-cell lymphomas. Within this context, our central focus is on the pharmacological inhibition of phosphodiesterase 4B (PDE4B). The role of PDE4B in lymphomas was first suggested when we found this gene to be prominently overexpressed in fatal/refractory diffuse large B-cell Lymphoma (DLBCL). PDE4B, the main phosphodiesterase in B-cells, functions by hydrolyzing and inactivating cAMP, a ubiquitous second messenger with marked growth inhibitory properties in normal and malignant lymphocytes. As PDE4B terminates cAMP activity, it abrogates these inhibitory effects. Notably, the translational potential of our studies is strengthened by the availability of FDA-approved PDE4 inhibitors for the treatment of non-malignant

conditions.With timely grant support from the IIMS/CTSA (1 pilot project and 2 TTR awards), we could expand our research and explore the interplay between cyclic-AMP/PDE4B signals and other survival pathways in malignant B-lymphocytes. These investigations are particularly relevant because they have the potential to identify targeted combinatorial approaches for the treatment of

lymphoma. In agreement with this concept, we uncovered that cyclic-AMP down-modulates the activity of the tyrosine kinase SYK, and showed that PDE4 and SYK inhibitors have synergistic anti-lymphoma activities (1). More recently, we discovered a significant association between the gene expression signatures of B-cell tumors overexpressing PDE4B and those with glucocorticoid resistance. Following this observation, we demonstrated that genetic or pharmacological inhibition of PDE4 restores glucocorticoid efficacy in lymphomas, via the highly specialized cyclic-AMP-mediated downregulation of AKT/mTOR signals (2). Importantly, these IIMS/CTSA supported studies played a fundamental role in our successful application for long-term funding support from the Cancer Prevention Research Institute of Texas (CPRIT), which should eventually lead to the clinical testing of PDE4 inhibitors for the treatment of human lymphomas.

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Rong Li, PhD – 1 Pilot Project, 2 TTR Awards

The IIMS/CTSA pilot funding has allowed us to address two important questions in cancer research. First, the funding supports an ongoing endeavor in the lab to elucidate the molecular distinction between normal and cancer stem cells. Cancer stem cells are cancer cells that share certain characteristics with normal stem cells. Accumulating evidence suggests that cancer stem cells contribute to therapeutic resistance, cancer recurrence, and metastasis. If a distinction in controlling self-renewal of these two stem cell populations can be found, it would be possible to destroy cancer stem cells without adversely compromising the physiological functions of normal stem cells.

In a separate IIMS/CTSA-funded project, we will be focusing on the molecular basis of functional distinction between two estrogen receptors, ERa and ERb, which share extensive sequence homology. However, unlike ERa ERb is considered as a tumor suppressor in breast cancer, as it inhibits breast tumor cell growth and its expression is associated with good prognosis. How the isotype-specific functions of ERb are achieved remains poorly understood. We will combine preclinical models and clinical samples to interrogate the isotype-specific regulation of ER function, an under-explored yet clinically important topic in endocrine and cancer research.

Christopher Frei, PharmD, MSc – 1 Pilot Project, 2010 KL2 Scholar

IIMS/CTSA funding is helping scientists and clinicians combat the MRSA “superbug” in South Texas. Dr. Christopher Frei, Assistant Professor at the UT Austin and the UT Health Science Center at San Antonio, has received two IIMS/CTSA grants to study patients with MRSA skin and soft tissue infections.

The first grant helped establish a clinical cohort in 14 family practice and internal medicine clinics from South San Antonio to North Austin. These clinics are part of the South Texas Ambulatory Research Network (STARNet). STARNet is one of several Practice Based Research Networks (PBRN) supported by the IIMS/CTSA. Nearly 250 patients have enrolled in the ongoing STARNet MRSA studies. Interim results have been presented at scientific meetings in Aspen, Boston, Vancouver, and Washington DC. An original research article is also scheduled to appear in the Journal of American Board of Family Practice later this year. This work has enhanced understanding of MRSA infections in South Texas and will lead to better risk-assessment and future treatments.

IIMS/CTSA funding is also helping to train Dr. Frei regarding the latest research methodologies. He was selected to participate in the KL2 Career Development Program. This program facilitates research partnerships between junior and established scientists in an effort to help the junior scientist hone their research skills to better compete for external research funding. This type of mentorship has helped Dr. Frei prepare two federal grant applications and compete successfully for two additional grant awards from the pharmaceutical industry.

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Amina Akoulouze Bika, PhD – 1 TTR Award, 2010 KL2 Scholar

I am extremely grateful for the awards from the IIMS/CTSA program (TTR and KL2). These awards helped to move my research career forward and to compete successfully for a K01 award from NIDDK (PI) and a VA grant (co-I), to publish my results (FRBM 2010, Exp. Gerontol. 2011, JCI to be submitted), and to submit new grant proposals (2 IIMS/CTSA, 1 SAAF, 1 ADA). My career goal is to establish myself as an independent investigator in basic and translational research in the area of oxidative stress and inflammation-related diseases, with a major focus on metabolic syndrome/type 2 diabetes. Despite available treatment, a significant number of diabetic patients are unable to achieve glycemic control and experience major complications. Therefore, there is a need for novel and complementary therapeutic approaches. I strongly believe that the elucidation of the role of NOX NADPH oxidases as a source of oxidative stress in metabolic syndrome/type 2 diabetes will aid in the design of novel strategies for the prevention and treatment of the disease and its related complications (diabetes, stroke, CVD, amputation, blindness, infertility). With the current development of specific inhibitors against each NOX isoform, our findings may well translate to man in the near future. To achieve this goal, since my background is mostly in basic research, these awards gave me protected time to get training in clinical investigation through the MSCI program.

Roman Kuranov, PhD – 1 Pilot Project, 2010 KL2 Scholar

My research is aimed to develop an innovative imaging instrument: functional Optical Coherence Tomography to provide early biomarkers and longitudinal monitoring of Diabetic Retinopathy

(DR). DR is the leading cause of blindness in people between 18 and 75 years old. The earliest stages of DR, when treatment of the disease is most effective, are characterized by defects in microscopic retinal blood vessels leading to poor nutrient delivery to the surrounding retinal tissues. Currently, ophthalmologists do not have the tools to detect small defects in microscopic blood vessels. My approach is capable of detecting the earliest abnormalities in retinal microvasculature oxygenation and flow before anatomical changes can be detected. Successful completion of my studies will improve understanding of disease progression characteristics and help prevent blindness in many DR patients. IIMS support through the KL2 and pilot mechanisms has allowed me to make substantial progress on my research and lay a solid foundation for verifying this approach in larger animal studies

and translate this technology to patients. Uses of KL2 resources have strengthened my optical expertise with clinical and physiological training and allowed me to acquire preliminary data in mouse brain arterioles. Using the IIMS pilot award I will optimize the instrument for retinal imaging. Having IIMS support has allowed me to apply for ADA Junior Faculty Award and R21 NIH grants and to publish one manuscript and to submit another manuscript to a leading biomedical journal.

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Scott Johnson, MD – 1 Pilot Project, 1 TTR Award

The Lung transplant program at UTHSCSA in partnership with University Hospital ranks among the top 7% in the world in terms of annual volume, and is complemented by a recently established research endeavor with a unique set of skills that allow performance of an orthotopic lung transplant in rats. The Lung Transplant Study group in the department of Cardiothoracic Surgery at UTHSCSA performs translational research using this rat lung transplant animal model in order to study and hopefully eventually ameliorate problems encountered in human lung transplant recipients. Such problems include rejection (and the development of newer immunosuppressive medications to prevent rejection), ischemia-reperfusion injury, and organ preservation. This combination of clinical experience and expertise along with proficiency in performing rodent lung

transplants allows easy translation of research findings to human patients, and allows clinical problems to be studied in a controlled lab environment. Research performed this far include the characterization and pharmacokinetics of inhaled nanoparticle tacrolimus, a novel formulation of a common anti-rejection medication, which can be delivered locally to the lungs yet remain undetectable in the blood and other solid organs. In a current study supported by a generous grant from the IIMS/CTSA, this line of work has been furthered so that the efficacy of this nanoparticle tacrolimus in preventing rejection in an allogeneic rat lung transplant can be studied. Preliminary results of this work show promising attenuation of rejection using this drug as measured by both histology and in the reduction of pro-inflammatory cytokines. In addition, another separate grant from the IIMS/CTSA will help further investigate (in this same animal model) the potential beneficial effect of this drug in preventing/attenuating ischemia-reperfusion injury, using a non-rejection (syngenic) rat lung transplant model. In this study, it is hypothesized that delivery of this novel drug to the donor rat prior to explantation will demonstrate improved blood gases, wet to dry weight ratios, reduced proinflammatory cytokines, and reduced myeloperoxidase activity once the treated lung has been implanted and reperfused in the recipient. In the future, the lab plans to investigate similar effects in a brain dead rat lung transplant donor model, and also study other anti-rejection drugs and newer formulations (e.g. nanoparticle rapamycin). In addition, delineation of the immunological pathways involved with lung transplant rejection will be studied in collaboration with other disciplines at the Health Science Center.

A rat lung transplant at necropsy showing grossly no rejection when compared to the native lung after five days of receiving the inhaled nanoparticle Tacrolimus

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LuZhe Sun, PhD – 1 Pilot Project, 1 TTR Award

Patients with metastatic prostate cancer are often treated first with androgen deprivation therapy, but will almost invariably develop androgen-independent prostate cancer. Currently, therapeutic approaches for androgen-independent prostate cancer are very limited and are only moderately efficacious. Part of the research program in Dr. LuZhe Sun’s laboratory is to elucidate how androgen-dependent prostate cancer becomes androgen-independent during androgen deprivation therapy. Studies from his group and by other investigators indicate that the hedgehog signaling pathway is activated when

androgen-dependent prostate cancer cells are cultured in an androgen-depleted medium, suggesting that increased hedgehog signaling may be a mechanism for the development of androgen-independent prostate cancer. The funding from IIMS/CTSA (1 pilot project and 1 TTR award) helped his group to further investigate how hedgehog signaling may promote the growth and survival of androgen-independent PCa cells and to examine whether the combination of anti-androgen therapy with a hedgehog inhibitor can inhibit the development and progression of androgen-independent prostate cancer in vitro and in vivo. The research has yielded several novel findings, which have allowed Dr. Sun to use them as preliminary data for his grant applications to NIH and CPRIT. The long term goal of this research is to determine if hedgehog inhibitors are efficacious in treating androgen-independent prostate cancer.

Cynthia Blanco, MD – 1 Pilot Project

My pilot project through the IIMS was designed to investigate Insulin Signaling and Glucose Metabolism in Prematurity. The results from this initial project have found significant developmental differences in the insulin signaling pathways and insulin insensitivity in prematurity. The importance of these findings relate to hyperglycemia, a highly prevalent condition in premature infants. Therefore, with the preliminary data obtained with this pilot project, I obtained a prestigious award from the Harold Amos Faculty Development Program by the Robert Wood Johnson Foundation to further advance this area or research. Furthermore, the American Diabetes Association has recently awarded me a basic science research grant to investigate the mechanism of impaired glucose metabolism in prematurity.

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Karen Block, PhD – 1 Pilot Project

Dr. Block received a Pilot Project Award (2009-2010) through the IIMS/CTSA entitled “Role of p22phox-mediated oxidative stress in renal carcinogenesis: Translational Applications” to study the role and expression of Nox oxidases in renal cell carcinoma. The IIMS/CTSA funding resulted in several prolific outcomes for the Principal Investigator. First, the IIMS/CTSA funding resulted in the genesis of a comprehensive renal tumor biorepository currently used by investigators at UTHSCSA to generate preliminary data that have been submitted or have led to competitive National funding. Second, the funding has fostered new collaborations and has resulted in strong productivity in the form of three first, and/or, senior author publications in solid impact factor journals. Thirdly, the published and preliminary data generated from the IIMS/CTSA funding was used by Dr. Block to submit two multi-investigator awards as co-investigator and will be used to renew her NIH / NCI R01 funding. Finally, the studies funded by IIMS/CTSA have supported the Dr. Block’s hypotheses that oxidative stress, mediated by Nox oxidases play a large and broad role in the development and progression of renal cancer. These findings have strong translational potential to lead to novel therapeutic targeting in the treatment of renal cell carcinoma.

Michael Brumlik, PhD – 1 TTR award

Toxoplasma gondii is a medically important, obligate intracellular parasite that is capable of causing life-threatening infections in immunocompromised hosts. Macrophages are of particular interest to us because they are known to facilitate the dissemination of T. gondii parasites throughout the infected host. Although T. gondii subversion of host cell signaling is well-described using in vitro models, global changes in host cell gene expression have never been directly examined in cells

from intact animals. We therefore wished to assess changes in the expression of more than 45,200 transcripts in splenic macrophages isolated from T. gondii-infected mice using the Illumina mouse v2 Whole-Genome Expression BeadChips (MouseWG-6 v2.0) platform. By using yellow fluorescent protein (YFP)-expressing parasites, we were able to separate infected from uninfected macrophages in spleens from infected mice prior to RNA isolation, purification, linear amplification, and microarray analysis. Uninfected splenic macrophages from naïve mice were likewise examined. The data collected from this study have defined which mouse transcripts are differentially regulated as a result of T. gondii infection. Several genes encoding members of the killer cell lectin-like receptor subfamily A, which are critical to effective cell mediated immunity, were significantly upregulated in YFP- (uninfected) macrophages from infected mice. Klre1, which encodes an important

member of the killer cell lectin-like receptor subfamily E, was likewise upregulated. Remarkably, within a subset of >1000 genes found to be differentially expressed between the infected and uninfected macrophages from infected animals, macrophages infected with T. gondii exhibited a transcriptional profile bearing much greater resemblance to that observed for macrophages isolated from naïve mice versus the transcriptional profile in uninfected splenic macrophages isolated from infected mice. Our findings highlight for the first time the extraordinary degree to which T. gondii suppresses infection-induced changes based on a direct comparison of infected versus uninfected cells in the same animal, demonstrating the exquisite ability of T. gondii to minimize detection by the host immune system.

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Adelita G. Cantu, RN, PhD – 2008 KL2 Scholar

Since receiving the KL2 scholar award, I have been enabled to continue with my health disparities research interest in understanding the socio-cultural and intra person mediators necessary for behavior change, particularly among older Mexican American women. I have received funding to understand how a group of Mexican American women with diabetes or at risk for diabetes use the internet to seek out health information and whether this information then informs their health choices. I have recently received funding to begin a pilot to understand why a group of senior Mexican American women, despite receiving multiple healthy nutrition classes at a west- side senior center still continue with their unhealthy choices in their diet. Because the health choices that people make greatly depend on the built environment, I have partnered with Metro Health and received funding from the Robert Wood Johnson Foundation Healthy Kids/Healthy Communities grant to understand how west-side residents use corner stores and how the addition of healthy items in their stores may inform choices about nutrition.

Relative to health disparities, literature also tells us that by encouraging the research careers of minorities will have an impact on health disparities reduction by having minority researchers designing and participating in studies that can contribute to the reduction. So in this vein, I am a co-PI on an R01 study called MESA: Mechanisms to Enhance Scholarly Achievement. The goal of the study is to engage inter-professional health students, particularly those from underrepresented groups, in community-based research projects and thus encourage their continued interest in research, particularly inter-professional community-based research.

Hongzhi Chen – 2010 TST Scholar

The title of my research project is “DsbA-L enhances insulin sensitivity by improving mitochondrial functions”. Obesity is associated with various metabolic diseases and has currently reached epidemic proportions in the western industrialized world. Our lab focuses on the study of insulin resistance, which is the culprit of obesity-related diseases such as Type 2 diabetes. Recently we identified a mitochondrial protein called DsbA-L, which is negatively correlated with insulin resistance. Furthermore, it plays beneficial roles in metabolism evident by in vitro and in vivo studies. My goal is to elucidate the mechanism by which DsbA-L exerts the beneficial effects especially in insulin response tissues such as fat and liver. Through screening studies, we identified some interesting interactions between this protein and other molecules in the mitochondria including respiratory subunits. Now I am

studying whether and how these interactions could result in healthier cells/animals. With the help of this funding, I have made significant progress on this project. Thanks to the help from the TST program, I received a pre-doctoral fellowship from American Heart Association. The experience I gained in this program will help me a lot in my academic future.

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Ying Ann Chiao – 2009 TST Scholar

The experience of the one-year translational science training greatly enhanced my understanding and interest towards translational research. The TST grant supported my dissertation project on ‘The Role of Matrix Metalloproteinase-9 (MMP-9) in Cardiac Aging.’ I demonstrated that levels of MMP-9 in plasma were elevated with senescence in mice. Interestingly, plasma MMP-9 levels were positively correlated with end-diastolic dimensions of the left ventricle and the levels of MMP-9 in the left ventricle. These findings suggest that MMP-9 is a potential plasma biomarker of cardiac aging, and were summarized in the article ‘Multi-analyte Profiling Reveals

MMP-9 and MCP-1 as Plasma Biomarkers for Cardiac Aging’ published in the journal Circulation: Cardiovascular Genetics. To further determine the role of MMP-9 in cardiac aging, I also compared the cardiac aging responses in MMP-9 null mice with wild-type mice, and showed that MMP-9 deletion can attenuate the age-related increase in myocardial collagen deposition and decline in diastolic function. I am currently preparing a manuscript based on these results. The TST grant provided critical funding support for my research project and the findings of the project may provide important therapeutic insight for patients with age-related diastolic dysfunction.

Addanki Pratap Kumar, PhD – 1 TTR Award

Despite significant advances in the efforts to develop novel targeted agents, the overall survival benefit for patients diagnosed with metastatic prostate cancer is less than 3 to 5 months with little to no impact on cancer regression. Although prostate specific antigen (PSA) has been a widely used serum-based test for prognosis of recurrent disease, the utility of PSA for prostate cancer diagnosis is limited. Our goal is to develop a panel of markers that can predict recurring disease. Using funding from the IIMS/CTSA we used immunohistochemical analysis to evaluate formalin-fixed and paraffin-embedded tissue samples from 72 prostate cancer patients (5 years after radical prostatectomy) for expression of six potential markers that were identified in our laboratory. 38 of these samples were classified as non-failures (with no recurring disease) and 34 as treatment failures (showing recurring disease as evidenced by rising PSA). Statistical analysis was performed to determine if these markers, either alone or in combination, can predict biochemical recurrence more accurately. Analysis of these data showed statistically significant differences in the expression of FLIP, an anti-apoptotic protein and Sp3, a transcription factor, between non-failure and failure samples. The combination of these two markers improved diagnostic ability significantly. Although preliminary, these findings warrant further evaluation using larger cohorts to confirm and validate these observations, as well as to understand the role of these two factors in the development of recurring disease. A manuscript describing these findings is currently in preparation. We will also use these preliminary data as part of the competitive renewal of a current RO1 grant in the summer of 2012.

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Sara Espinoza, MD, MSc – 2008 KL2 Scholar

Dr. Espinoza’s work focuses on the geriatric syndrome of frailty, which is characterized by vulnerability to decline and disability in older adults as they age. Her work, supported by the KL2 award, examined the frailty phenotype in the San Antonio Longitudinal Study of Aging (SALSA), with the mentorship of Helen Hazuda, Ph.D., the Principal Investigator of SALSA. Her work focused on identifying plasma biomarkers of frailty, and her laboratory developed a methodology for isolating plasma glycoproteins in human plasma, with the mentorship of Arlan Richardson, Ph.D., Director of the Barshop Institute for Longevity and Aging Studies. Dr. Espinoza’s KL2 award led to a four-year research award from the Robert Wood Johnson Foundation to continue studying frailty in SALSA, a longitudinal cohort study of older adults in San Antonio. Her current work focuses on ethnic differences in frailty and disability, and is beginning to assess on the role of diabetes in the development of frailty.

Maria Danet Lapiz-Bluhm, PhD, RN - 1 Pilot Project

The Institute for Integration of Medicine and Science Clinical and Translational Science Award (IIMS/CTSA) Pilot Project funding for my study, “Alterations in hypothalamic-pituitary-adrenal (HPA) axis in postwar and civilian trauma posttraumatic stress disorder (PTSD)” helped transition my pre-clinical rodent-based research on the effects of stress to patient-oriented research on PTSD. The pilot project aimed to characterize the involvement of the HPA axis in PTSD through the use of salivary cortisol and dihydroepiandrosterone (DHEA) to provide better understanding of the role of this neurohormonal system in PTSD. The results

have indicated a differential pattern of activation of the HPA axis in individuals with PTSD compared with normal controls. Pilot results were presented at the Western Institute of Nursing annual conference in Las Vegas, NV, and a manuscript is in preparation for publication. The project has helped my development as a translational scientist, as it provided opportunity to conduct clinical research, which has its unique challenges, strengths and limitations compared with rodent-based research. The funding was instrumental in my successful applications for the Hogg Foundation Mental Health Research Grant to characterize the sympatho-adrenal system (SAS) activation in PTSD, and the Mentored Research Development (KL2) Program in Clinical and Translation Science to characterize changes in HPA, SAS and neurotrophic systems in military service personnel exposed to combat upon return from deployment. The results from the pilot study will also serve as my preliminary data for other National Institutes of Health funding applications.

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Jane Lynch, MD and Carisse Orsi, MD – 1 TTR Award

Below is the summary of our research. The primary investigator is Dr. Carisse Orsi, a new addition to our faculty following the completion of her fellowship at UTSCSA in July 2010. This is very exciting work that was presented in preliminary form at the American Diabetes Association meeting. Non-alcoholic fatty liver disease (NAFLD) is a recently recognized serious medical complication of obesity in youth. It is more prevalent among insulin-resistant Hispanic youth. Vitamin D insufficiency contributes to insulin

resistance. We are completing a trial using magnetic resonance imaging and spectroscopy (MRS) to study vitamin D-insufficient children diagnosed with significant NAFLD. Our study assessed MRS-quantified NAFLD changes following vitamin D normalization over six months. The IIMS/CTSA funding supported our collaboration with the Research Imaging Institute, which performed and interpreted these MRS scans. This research has allowed us to

accurately quantify NAFLD changes and to explore the potential vitamin D association with this disease. Preliminary data suggest positive changes and a concern that we are underestimating the degree of this serious condition in at-risk children. We hope to further our study of other critical factors leading to the risks for pediatric NAFLD by establishing normative data among non-obese Hispanic children.

Jane Lynch, MD Assoc Professor of pediatrics

UTHSCSA

Carisse Orsi, MD Pediatric Endocrine Fellow

UTHSCSA

Ketan Marballi – 2010 TST Scholar

As one of the IIMS-CTSA TST scholars, I can honestly say that TST award has opened many exciting opportunities for my research and professional development. Under the guidance of my mentor, Dr. Walss-Bass, the focus of our research is identifying molecular markers in mental disorders. With the funding made available from the TST award, we were able to carry out post- mortem brain research in collaboration with the Southwest Brain Bank. We are currently studying alterations in processing (cleavage) of neuregulin 1 (NRG1), a protein with numerous functions in the nervous system and one of the most associated susceptibility genes for psychiatric disorders. Through my research we were able to show that abnormalities in cleavage occur across diagnoses (schizophrenia and bipolar disorder) and may arise due to dysregulation of enzymes associated with cleavage

such as BACE1 and ADAM17. We are in the process of submitting a manuscript on these results. Through the TST award, we have also expanded our research to animal models of behavior where we will be studying BACE1 knockout mice and the pathways leading to alterations in behavior. This research will give us more insights into how altered NRG1 cleavage may lead to schizophrenia and develop NRG1 as a therapeutic target for behavioral disorders.

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Carlos Orihuela, PhD – 1 TTR Award

Streptococcus pneumoniae, a Gram-positive bacteria, is the leading cause of community-acquiredpneumonia and infectious death in the elderly. We have determined that invasive isolates of S. pneumoniae carry a protein called PsrP (Pneumococcal Serine-rich repeat protein) that mediates attachment to lung cells and the formation of bacterial biofilms in vivo. Importantly, a small section of PsrP called the Basic Region (BR) is responsible for these virulence activities. The goal of the Translational Technology Supplement award through the IIMS/CTSA was to determine the structure of the BR domain of PsrP such that we could better understand its interaction as a lung cell and intra-species adhesion. At this time we have obtained BR crystals and are in the process of determining the structure.

Theresa Powell, PhD - 1 Pilot Project

As a new faculty member, the IIMS pilot award to study omega3 supplementation in high-risk pregnant women was a great impetus for a rapid start of our research program at UTHSCSA. The award came just as we were moving our research team from University of Cincinnati to San Antonio, which meant we learned the procedures for clinical research in our new home as quickly as possible and were up and running in a few months time. The pilot award, along with the enthusiasm of the IIMS and FORU staff, provided a tremendous spark for the development of our outstanding clinical research team. The IIMS award was extended by an NHLBI funded

R21 pilot study to broaden our recruiting goals to include women with gestational diabetes and high BMI. We have now established our recruiting protocol in five UHS prenatal clinics and we are continuing to successfully accomplish the goals of the study. To date, a total of 46 women have been enrolled and 33 of these have completed the full protocol. We have now established that dietary omega3 fatty acid intake is extremely low in our predominantly Hispanic study population. Our hypothesis is that omega3 supplementation during the second half or pregnancy in obese pregnant women with and without gestational diabetes will increase insulin sensitivity, reduce inflammatory markers and improve placental function. Preliminary evaluation in 25 subjects suggests that omega3 supplementation during high risk pregnancy may improve maternal adiponectin levels and reduce her fasting insulin and HOMA-IR scores. Furthermore, our preliminary studies indicate that omega-3 supplementation in obese pregnant women resulted in a normalization of placental function. The data from these pilot studies provides the foundation for a RO1 grant that is currently being prepared.

L-R: Evelyn Miller, RN; Nancy Sanchez; Theresa Powell, Phd;

DHA team L-R: Agnes Yu Hunter, BS - nutrition student; Christiane Meireles, PhD, study dietitian; Evelyn Miller, RN, study coordinator; Vanessa Ramirez, MS Laboratory supervisor; Tatiana Cordova, MD, Research Area Specialist

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Anand Ramasubramanian, PhD – 1 Pilot Project

Candidiasis, a fungal disease caused by Candida albicans, is now the fourth most frequent nosocomial infection in hospitals worldwide. Disseminated candidiasis carries unacceptably high mortality rates of nearly 50%, with an added cost of approximately $2-4 billion annually in the US alone. It remains a threat to human health as a consequence of AIDS, steroid therapy, organ and tissue transplantation, cancer therapy, broad spectrum antibiotics and other immune defects. One of the important reasons for the inefficacy of existing antifungal drugs is that the majority of manifestations of candidiasis are associated with biofilm formation. Biofilms display high levels of resistance to antifungal agents, are protected from host defenses, and have the potential to initiate or prolong

infections by providing a safe sanctuary from which organisms can invade local tissue, seed new infection sites and resist eradication efforts. We have developed a microarray-based fungal nanobiofilm chip employing Candida albicans, called Candida albicans Biofilm Chip or CaBChip, for rapid, robust, reproducible and inexpensive screening for novel anti-fungal drug candidates, and have prototyped the screening with a library of small molecule compounds. We are now collaborating with the US Army to adapt the platform for screening drugs against polymicrobial dental and wound infections. (Figure: CaBChip with a rectangular array of C. albicans nanobiofilm containing different morphological forms of the fungi).

Sarah Ullevig – 2010 TST Scholar

My research focuses on uncovering the roles oxidative stress plays in monocyte migration and the development of atherosclerosis and the mechanism through which natural compounds, i.e. phytochemicals, protect against monocyte dysfunction and atherosclerosis in mice. The financial support provided by the Translational Science Training (TST) Scholarship allowed me to develop novel techniques in redox proteomics that significantly contributed to the advance my research project. These techniques utilize fluorescent or biotinylated tags that specifically detect glutathionylated proteins and will be essential for many applications in my project and future publications. In addition, the TST funds allowed for purchase of needed antibodies to uncover the mechanism of the phytochemicals in monocyte migration, including, but not limited to, the upregulation of glutaredoxin-1,

the enzyme the catalyzes the disulfide reduction of gluathionylated proteins. The support from IIMS also provided me the opportunity to attend scientific meetings. This year, because of the TST scholarship, I was able to attend and present an oral presentation at the Experimental Biology Meeting in Washington DC. With this opportunity, I not only presented my work, but networked and met other scientists working in my field. In summary, the TST scholarship has expanded my breadth of experience in presenting at scientific meetings and provided funds that have advanced my research goals leading to publishable data.

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Sue Stacy, PhD – 1 TTR Award

Defining T regulatory cell phenotypes to be targeted for immune and autoimmune therapies Funding of this project facilitated studies of regulatory T cells (Tregs) in three different animal models. First, for assessing their role in autoimmune myasthenia gravis (MG), two genetically manipulated mouse lines were used: i) a foxp3 (a Treg-specific transcriptional regulator) GFP reporter and ii) a transgenic line in which T cell tolerance is elicited to TAChR, the MG inducing antigen. The pilot funding allowed us to optimize FACS protocols in order to obtain antigen-specific Treg populations; as shown below, the Tregs were then tested for their ability to suppress effector cells specific for the immunodominant TAChR peptide. Second, the immunomodulatory and lifespan enhancing drug rapamycin reportedly enhances Tregs in vitro. Thus, we asked whether changes in this suppressive cell subset would be seen in mice fed a diet including rapamycin and then immunized with either the TAChR peptide, a protein antigen, or intact viable bacteria. No significant changes in Tregs were seen [these studies were performed by Adrianna Benavides, a graduate student of collaborator, Dr. Ellen Kraig]. Lastly, serological reagents were tested to facilitate measurements of Treg populations in young and old non-human primates including baboons, rhesus, and African green monkeys [these studies were performed by Ms. Lourdes Arteaga-Cortes].

The data generated from this project contributed to a NIA R36 grant proposal submitted by Adriana Benavides entitled “Long-term rapamycin differentially affects immunity in young and old.” In addition, future NIH/NIA or NIH/NIAID grant application submissions to which this work is likely to contribute include: 1) a grant designed to test the effects of the Treg-enhancing drug rapamycin on autoimmune responses; and 2) a grant addressing immune tolerance in the TAChR transgenic MG models. The information from these studies also contributed to abstracts presented at national meetings including: Lourdes Arteaga-Cortes, Jessica Mayeux, Angelene Cantwell, Amanda Pasquali, Sue Stacy, Peter Dube, Karen Rice, and Ellen Kraig. Effects of aging on B and T cell immunity in nonhuman primate (NHP) species. J. Immunol., 2010; 184: 43.20. Poster presentation. Adriana Benavides, Elizabeth Fernandez, Z. Sharp, Randy Strong, and Ellen Kraig. Treg and rapamycin effects on humoral immunity in young and old mice. J. Immunol., 2010; 184: 84.12. Poster presentation.

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Rene Renteria, PhD - 1 Pilot Project

The main goal of our laboratory is to understand how diabetic retinopathy causes progressive loss of vision. Our IIMS Pilot Project set out to test the hypothesis that the drug rapamycin would protect vision in an animal model of diabetes because of the drug’s action on numerous important cellular pathways.

The data we obtained as a result of this funding form a critical part of two major grant submissions that are currently under review. One is a five year, R01 level proposal to the National Eye Institute, and the other is a proposal for a three

year Junior Faculty Award from the American Diabetes Association. In addition, data from the pilot project are part of a manuscript that is currently in revision and another that is in preparation. Garnering funding and publishing papers are both major and necessary steps to allow our research to move forward. Only by the collective efforts of the research enterprise will we be able to cure this costly complication of diabetes, which is the leading cause of blindness in working-age adults in the US.

Suzette Tardif, PhD – 1 Pilot Project

Development of a nonhuman primate model of age-related functional decline. Suzette Tardif, Sara Espinoza, Corinna Ross - Barshop Institute for Longevity & Aging Studies.

The purpose of this project was to develop a set of tests for assessing muscle function and coordination in marmoset monkeys and to determine whether these functions decline with age. Human aging effects are often defined, not by presence of disease or pathologies, but by decline in motor and cognitive abilities. However, tests in animals comparable to those done to determine frailty in humans have been extremely limited.

We developed and validated a pulley task (see illustration) to assess upper body strength and a conveyor belt task to assess fine motor coordination and executive function. Most marmosets could be trained to reliably perform these tasks, using positive reinforcement, within a matter of weeks. Future analyses will determine whether old versus young marmosets differ in performance ability. These tests may then also be applied to models in which animals have undergone treatments designed to either impair or correct motor skills.