Diabetes COBRE

SECTION OF ENDOCRINOLOGY AND DIABETES
UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER
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Pilot Projects


P
roject Title: "Underlying Mechanism of PPARα in Treatment of Diabetic Retinopathy"
PJI:  Ying Chen, PhD -Year 4 & 5

 Ying Chen, PhD was trained as ophthalmologist and received her Ph.D. from China in Ophthalmology at 2001.  She then did post-doctoral studies at the Medical University of South Carolina, the Scripps Research Institute and the University of California at Berkeley.  She gained extensive experience in the field of diabetic retinopathy and the aged related macular degeneration.  In October of 2003, Dr. Chen joined the section of endocrinology at the University of Oklahoma Health Sciences Center as a postdoctor. She was promoted to research instructor at 2008. She received 3 grants and had over 35 publications in peer reviewed journals.

Project Title: "ER Stress Response and Autophagy in the Onset and Progression of Diabetes"
PJI:  Franklin A. Hays, PhD, Mentor: Paul Weigel, PhD, -Year 5

hays Franklin A. Hays, PhD is an Assistant Professor in the Department of Biochemistry and Molecular Biology at the University of Oklahoma Health Sciences Center.   He received his Ph. D. in biochemistry and biophysics from Oregon State University in 2005 in the laboratory of Dr. P. Shing Ho.   Following completion of his graduate training Dr. Hays joined Dr. Robert Stroud's group at the University of California in San Francisco (UCSF) to study integral membrane protein structure and function.  During this time Dr. Hays was the recipient of multiple postdoctoral fellowships, including a 3-year Ruth L. Kirschstein National Research Service Award from the NIH, and published several papers in top rated journals including Science.  Dr. Hays joined the OUHSC faculty in August of 2010 and his laboratory is currently focused on understanding the underlying mechanisms of drug disposition and response in the treatment of human disease.  These efforts employ a diverse array of techniques ranging from biophysical, molecular, cellular, and whole animal characterizations.  Recently, Dr. Hays has initiated studies aimed at understanding how cells respond to stress within the diabetic state.  This stress can be induced from numerous external stimuli, such as high blood glucose concentrations, and illicit an equally broad range of cellular response pathways.  Efforts by the Hays laboratory under within this new research direction will be facilitated by interactions with established mentors on the OUHSC campus and within the Harold Hamm Oklahoma Diabetes Center.  

Project Title: "Mechanisms of mitochondrial dysfunction in diabetic cardiomyopathy"
PJI:  Kenneth M. Humphries, Ph.D.  Year 3 & 5

Kenneth M. Humphries, PhD is an Assistant Member at the Oklahoma Medical Research Foundation (OMRF) in the Free Radical Biology and Aging Program, and an adjunct Assistant Professor in the Departments of Biochemistry and Molecular Biology and Geriatric Medicine at the University of Oklahoma Health Science Center.  Dr. Humphries received his Ph.D. from Case Western Reserve University in the Department of Physiology and Biophysics.   For his graduate work, he characterized an important and novel mechanism of mitochondrial dysfunction induced by lipid peroxidation.  This work culminated in two important papers in the journal Biochemistry that, combined, have been cited more than 300 times.  Dr. Humphries did his postdoctoral work at the Howard Hughes Medical Institute, University of California San Diego, with Dr. Susan Taylor.  He used this training to expand his interest in free radicals beyond their involvement in oxidative damage and into their role in redox regulation.  His work at UCSD highlighted a novel aspect of cAMP-dependent protein kinase regulation related mediated by protein thiol redox status.  Dr. Humphries’ training and expertise are a natural fit for addressing important questions in the field of diabetes. Specifically, diabetic cardiomyopathy is a serious and deadly complication of diabetes, and understanding how this occurs at the molecular level is critical for future therapeutic treatments and prevention. It is known that diabetes is associated with deficits in mitochondrial function and increased free radical production, but the cause and effect relationship is not well understood.  Thus, he is currently focusing on the identifying the diabetes-induces changes that occur to heart mitochondria prior to the onset of cardiac complications.  Preliminary work in his laboratory has demonstrated remarkable metabolic pathologies in heart mitochondria using a rodent model of type 1 diabetes.  The results of this project will have important implications for understanding the molecular basis of diabetic cardiomyopathy. 

Project Title: "VEGF signaling in photoreceptors."
PJI:  Yun Z. Le, PhD -Year 4-5

The discovery of vascular endothelial growth factor (VEGF) as a major angiogenic and vascular permeable factor has led to intensive studies on the physiological and pathological role of VEGF in regulating blood-retina barrier (BRB) function. As a result, anti-VEGF agents have become a major therapeutic strategy for BRB dysfunction in diabetic retinopathy (DR) and wet age-related macular degeneration (AMD). However, VEGF may be a survival factor for neurons. VEGF has been recognized as a protective factor in retinal neurons neuronal growth, differentiation, and survival in the central nervous system. While VEGF receptors are present in retinal neurons under normal and diabetic conditions, little is known about the role of VEGF in the survival of these neurons and current literatures are still controversial. As anti-VEGF strategy has become a major strategy for DR, revealing the role of VEGF in retinal neuron survival is paramount to the safety of long-term anti-VEGF treatments. It is known that diabetes induces photoreceptor dysfunction, particularly for cone photoreceptors that are mainly responsible for color and daytime vision. It is also well established that diabetes causes oxidative stress and ischemia that are possible reasons for VEGF up-regulation. Up-regulating VEGF under these stresses may be a survival mechanism for retinal neurons. To test our hypothesis that VEGF signaling plays an important role in photoreceptor survival and function under diabetic or ischemic conditions, we will determine the role and mechanisms of VEGF-signaling in photoreceptor integrity under ischemic and diabetic conditions. In this pilot study, we will perform a variety of biochemical, cellular, pathological, and physiological experiments using in vitro system and rod- or cone-specific VEGF receptor 2 knockout mice. A major goal of this pilot project is to establish animal models and to obtain preliminary data for a competitive NIH project grant application.

Project Title: “Impact of Age and Exercise on Insulin Action”
PJI: Kevin R. Short, PhD - Year 5

   Kevin Short, PhD obtained graduate training in human exercise physiology, metabolism and muscle biochemistry at Purdue University and Ball State University.  He then completed post-doctoral work in endocrinology, diabetes, and aging at Mayo Clinic, before joining the faculty of the Mayo School of Medicine for four years.  At Mayo Dr. Short developed expertise in measuring energy expenditure, protein and glucose metabolism with stable isotope-labeled tracers and tissue biochemistry in humans and animals.  In 2006 Dr. Short joined the Department of Pediatrics in the Section of Diabetes and Endocrinology.  Dr. Short’s current research examines the impact of exercise on insulin sensitivity and vascular health, particularly in sedentary adolescent children.  The goal is to identify the most effective means to prevent or reverse the cardiometabolic risk in children and young adults, thereby limiting a potential lifetime of pathology and medical burden.  The team has several years of experience in exercise physiology and has directed exercise training and metabolic outcome studies.  Dr. Short and colleagues developed the new Metabolic Research Program, located in the brand new OU Children’s Physicians Building.  This program goals and facilities were developed for performing clinical and basic science investigations related to the problem of obesity and diabetes in children and adolescents, with the capacity to conduct exercise testing and training, body composition, vascular function and biological sample analyses.  Dr. Short’s CoBRE-supported work has examined how insulin action is affected by a single session of exercise in children versus young and elderly adults, and how different intensities of aerobic exercise training may differentially affect insulin sensitivity and vascular function in overweight sedentary adolescents.  New research plans include employing exercise to reduce metabolic risk in people with spinal cord injury and measuring the impact of physical activity on the concentration and turnover of multiple cardiovascular risk proteins in circulation.

Project Title:  "Activation of AMPK protests against diabetic vascular complications"
PJI: Zhonglin Xie, MD, PhD Mentor: Ming-Hui Zou, MD, PhD - Year 5

 Zhonglin Xie, MD, PhD is an Assistant Professor in the Department of Medicine, Section of Endocrinology, the Oklahoma University Health Sciences Center. He received his PhD in Hokkaido University, Japan, and had an outstanding postdoctoral research experience in Boston University and University of Tennessee, during this period he was supported by a postdoctoral fellowship from the American Heart Association. Dr. Xie is very productive with over 40 publications, including 12 since 2001 in high impact journals such as Circulation, Circulation Research, Diabetes, J Biol Chem, and Hypertension. He has made the important discovery that protein kinase C- zeta regulates LKB1-AMPK cascade by increased LKB1 phosphorylation at Ser 428 and Ser 307, the latter being a newly identified phosphorylated site. His expertise in molecular biology and physiology will be applied to independent studies on the mechanisms by which AMPK activation protects against cardiovascular complications in diabetes. His studies will yield novel information of how AMPK is regulated in diabetes and if AMPK is a therapeutic target in preventing or delaying cardiovascular complications in diabetes.

Project Title: "Anti-autonomic receptor antibodies in diabetic orthostatic hypotension"
PJI:  Xichun Yu, MD: -Year 4

Xichun Yu, MD's current research focuses on the pathological roles of receptor-activating autoantibodies in cardiovascular diseases including hypertension, cardiomyopathy, metabolic syndrome and atrial fibrillation associated with hyperthyroidism. This pilot study examines the association of anti-autonomic receptor antibodies with orthostatic hypotension and characterizes the functional activity and impact of these antibodies. Orthostatic hypotension is often associated with diabetes and has many causes. It causes falls and injury, impaired quality of life and complicates concurrent medication use. These consequences are exaggerated in the diabetic patient and lead to patient and physician frustration because the therapeutic options have side effects and are frequently ineffective. There has been no significant breakthrough in understanding the etiology of orthostatic hypotension over the last 15 years. Dr. Yu, who works closely with Dr. David Kem, and his group are the first to look for and identify the presence of functionally active autoantibodies to the autonomic receptors in diabetic patients complicated by orthostatic hypotension. These autoantibodies produce a vasodilatory effect in vitro, suggesting that they may contribute to the pathogenesis and increased frequency of orthostatic hypotension associated with diabetes. Although the antibodies are unlikely the sole cause, they are important co-culprits in the complex cardiovascular pathophysiology of orthostatic hypotension. Data from this study will help identify therapeutic strategies that target these antibodies and also establish a priority for NIH funding for research on this clinical association.

 
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