The General Clinical Research Center (GCRC) and the Clinical and Translational Research Institute (CTRI) awarded 4 one-year pilot projects and 2 K-12 awards for the 2009 funding round.  The recipients are:

Clinical Awards (2 awards at $25,000 each)

Awardee:  Maple Fung, MD
Effects of variation in the degree of African admixture on renal disease and candidate adrenergic genes in African-American veterans.

Abstract  In the United States, African-Americans carry a high burden of kidney disease1. Because kidney disease has strong familial relationships2, genetic studies are important, though they are often confounded by complex ancestral genetic backgrounds3. Genetic admixture analyses assist in the determination of genetic contributors to phenotype differences between racial groups and facilitate the identification of genetic differences in complex phenotypes, such as renal disease. Though previous analyses have shown that African-American populations typically contain an average of 20% European admixture4, individual admixture estimates (IAEs) range from subjects with almost complete African ancestry to those with a very high degree of European admixture. Using ancestry-informative markers (AIMs), we will determine IAEs in African-American subjects recruited from a primary care veteran population with essential hypertension. In this study, these estimates will be used to evaluate the effect of ethnicity by genetic admixture on both the risk of renal disease alone and on potential candidate genes polymorphisms within the adrenergic and reninangiotensin systems (RAS) and their risk for renal disease. This invaluable resource of determining AIMs and IAEs will be accessible for use in future studies with this cohort and others that utilize similar genetic markers.

Awardee:  Karen Herbst, MD, PhD
Blockade of Receptor Cleavage in Diabetes Mellitus with an MMP Inhibitor

Abstract:  Obesity and type 2 diabetes mellitus (DM2) are epidemic. Development of obesity is associated with extensive modifications in adipose tissue including adipogenesis, angiogenesis and extracellular matrix proteolysis. Matrix metalloproteinases (MMPs) are a family of resident tissue enzymes that participate in these processes.  We identified a new mechanism of insulin resistance where elevated MMPs in the spontaneously hypertensive rat (SHR) cleave extracellular domains of receptors including the insulin receptor resulting in hyperglycemia. Activated MMPs therefore cause insulin resistance in an experimental model of the metabolic syndrome with DM2. Hyperglycemia and receptor integrity were dramatically improved after administration of the broadspectrum MMP inhibitor, doxycycline. In this proposal, we will test the novel hypothesis that reduction of activated MMP levels (by chronic doxycycline administration) serves to restore insulin receptor integrity and improves measures of diabetes in an obese population of human subjects with DM2.

Translational Award (1 award at $25,000)

Awardee:  Kimberly Newton, MD
Fecal Microbiome Analysis Utilizing 454-Pyrosequencing of 16S rRNA Genes in Children with Celiac Disease.

Abstract:  This pilot and feasibility proposal focuses on the relationship between celiac disease (CD) and the fecal microbiome in children. The overarching hypothesis is that the fecal microbiome composition changes with the inflammatory milieu of active CD, and thus is different in children both before and after treatment with gluten-free-diet (GFD), and compared to their healthy unaffected sibling controls. It is known that commensal bacteria can enhance immune homeostasis by suppressing pro-inflammatory epithelial signaling, and may provide a ‘barrier effect’, protecting host from intruding pathogens; in addition, perturbations of this commensal microbiome, termed dysbiosis, have been shown to be involved in pathogenesis of diseases associated with immune dysregulation. It is therefore plausible that the gastrointestinal microbiome composition plays a permissive or protective role in CD pathogenesis, which is an autoimmune disease characterized by aberrant
Th1 proinflammatory response and increased gastrointestinal permeability.  In order to begin to investigate this possibility further, the microbiome in patients with CD needs comprehensive characterization in both active and inactive disease states.  Therefore, using a prospective design, we will comprehensively characterize the fecal microbiome in children with CD before and after institution of a GFD, and compare that microbiome to healthy unaffected sibling controls utilizing the cutting-edge, high throughput, culture-independent technique of barcoded 454-pyrosequencing
of bacterial 16S rRNA genes. 

Innovative Technology (1 award at $50,000)

Awardee:  Richard Schwab, MD
Development of an Oxidative Stress Biomarker to Advance Dietary Interventions for Cancer Prevention.

Abstract:  Compounds in the diet can prevent cancer by activating the protective oxidative stress pathway without increasing damaging reactive oxygen species.  Ex vivo exposure of white blood cells to compounds known to activate the oxidative stress pathway will allow for the identification of a robust blood-based biomarker of this pathway.  Such a biomarker can then be preliminarily validated by comparing RNA stabilized buffy coat from subjects on strong inducers of oxidative stress (specifically chemotherapy[1]) to controls.  Since both chemotherapy and dietary constituents activate the Nrf2 pathway by altering the free thiol groups on KEAP1, releasing Nrf2 and allowing it to translocate to the nucleus (see Figure #1,) an Nrf2 specific biomarker should detect either type of activation.  Dietary constituents with putative chemopreventative activity can adduct the free thiols on KEAP1 releasing Nrf2[2-4].  Chemotherapy, in particular aromatic compounds like doxorubicin, generate reactive oxygen species that oxidize KEAP1 free thiols[5, 6], also releasing Nrf2.

K12 Award (2 awards)

Taylor Alan Doherty
Department of Medicine

Project Title: Targeting OX40/OX40L as a novel therapy for chronic asthma and remodeling

Abstract
Approximately 7% of the US population has asthma, representing a significant public health and economic burden.  Allergic asthma is thought to be orchestrated by cells of the immune system termed “T cells” that respond inappropriately to inhaled allergens.  The normal non-allergic immune system develops tolerance to these environmental allergens, but allergic individuals have T cells that remain reactive.   One molecule that appears to be critical to the development of these reactive T cells is OX40.  I will be studying the role of  OX40 using an animal model of chronic asthma as well as in samples from patients with allergic asthma.   Our hypothesis is that blocking OX40 will reduce allergic responses and perhaps lead to future treatments for this disease.

Sonia L. Ramamoorthy, MD
Department of Surgery

Project title: Neoplastic Transformation in Squamous Cell Cancer of the Anus

Abstract
Squamous cell cancer of the anus (anal cancer) is increasing in frequency in the general population in the United States, Europe and South America. Infection with “high risk” serotypes of human papillomavirus (HPV), HPV 16 and HPV 18, play a causative role in the development of anal dysplasia, a precursor lesion to anal cancer. What is poorly understood is the transformation from conditions of dysplasia to invasive cancer. We propose to examine a cohort of patients with anal dysplasia and anal cancer from our institution in whom we have obtained clinical data, including oncologic outcomes and risk factors such as tobacco usage, HIV disease, and molecular and inflammatory data directly from formalin fixed tissue. Our first aim is to study the inflammatory events involved with anal cancer and how this impacts clinical outcome. Our second aim is to investigate the role of a synchronous viral pathogen, JC virus, that is found within the GI tract and its role as a co-factor with HPV in neoplastic transformation from anal dysplasia to invasive anal cancer. Elucidating the process by which these cells undergo transformation will aid in our understanding of viral oncogenesis, and cell immunity in anal cancer development as it relates to cancer outcomes.