Role of Endoplasmic Reticulum Stress in Obesity-Related Endothelial Dysfunction
Principal Investigator: CHRISTOPHER GENTILE
Abstract: DESCRIPTION (provided by applicant): CANDIDATE: The candidate, Christopher L. Gentile, Ph.D., is a physiologist in the Department of Human Nutrition and Food Science at Colorado State University. Dr. Gentile's research focuses on the role of endoplasmic reticulum (ER) stress in metabolic diseases, and most recently, in the development of endothelial dysfunction. His immediate goal is to continue his postdoctoral training in order to acquire the research and professional skills necessary to successfully transition to an independent investigator. His long-term goal is to develop a successful independent, extramurally-funded research program that utilizes a translational approach (molecules to humans) to examine the molecular basis and clinical implications of ER stress in metabolic diseases. The proposed KO1 award will provide Dr. Gentile the necessary support to achieve this goal. CAREER DEVELOPMENT PLAN: Dr. Gentile's career development training in the present application consists of: 1) acquiring new research skills associated with and complementary to the proposed research plan;and 2) structured activities, including formal course-work, attendance and presentations at weekly journal clubs, university seminar series and scientific meetings, and regular interactions with his mentoring team. ENVIRONMENT: The environment for Dr. Gentile's training plan will be outstanding. The primary mentor, Dr. Pagliassotti, and co-mentor, Dr. Seals, are both internationally recognized, extramurally-funded scientists with strong records of successful mentoring in biomedical research pertaining to metabolic disease. They are complemented by an exceptional group of consulting mentors that consist of well-established investigators, each providing specific expertise in a key area of Dr. Gentile's research project and overall training plan. RESEARCH: Endothelial dysfunction is an independent risk factor for both type 2 diabetes and cardiovascular disease. The overall aim of the research project is to test the novel hypothesis that ER stress plays a role in the development of endothelial dysfunction related to metabolic diseases and lipid abnormalities. The proposed research will utilize a translational approach (molecules to humans) to examine this issue. Aim 1 will examine the mechanisms by which saturated fatty acids induce ER stress in cultured human endothelial cells, and determine whether ER stress directly mediates endothelial cell dysfunction and death. Aim 2 will examine if a high saturated fat diet induces ER stress in the vasculature of male Wistar rats, and if so, whether this ER stress mediates endothelial dysfunction that results from such a diet. Aim 3 will examine if vascular ER stress is present in obese individuals, and whether a high saturated fat meal induces vascular ER stress in lean individuals and causes a further elevation in obese individuals. Collectively, these studies could identify a novel mechanism underlying the development of endothelial dysfunction. The uniquely translational approach taken in this proposal will allow Dr. Gentile to simultaneously explore the molecular link between ER stress and endothelial dysfunction and determine the clinical implications of this link.
Funding Period: 2010-05-01 - 2015-04-30
more information: NIH RePORT
- Experimental evidence for therapeutic potential of taurine in the treatment of nonalcoholic fatty liver diseaseChristopher L Gentile
Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, Colorado 80523, USA
Am J Physiol Regul Integr Comp Physiol 301:R1710-22. 2011..Our results indicate that dietary supplementation with taurine offers significant potential as a preventative treatment for NAFLD...
- Fatty acid-mediated endoplasmic reticulum stress in vivo: differential response to the infusion of Soybean and Lard Oil in ratsAngela M Nivala
Department of Food Science and Human Nutrition, Colorado State University, Fort Collins, CO 80523 1571, USA
Metabolism 62:753-60. 2013....
- Activation of the unfolded protein response in vascular endothelial cells of nondiabetic obese adultsRachelle E Kaplon
Department of Integrative Physiology, University of Colorado, Boulder, Colorado 80309, USA
J Clin Endocrinol Metab 98:E1505-9. 2013..However, despite the well-established role of the vascular endothelium in obesity-related cardiometabolic dysfunction, it is unclear whether the UPR is activated in endothelial cells of obese adults...
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