The Role of Endoplasmic Reticulum Stress in Obesity-Related Endothelial Dysfuncti

候选人：Christopher L. Gentile博士，科罗拉多州立大学人类营养与食品科学系的生理学家。Gentile博士的研究重点是内质网（ER）应激在代谢性疾病中的作用，以及最近在内皮功能障碍发展中的作用。他的近期目标是继续他的博士后培训，以获得成功过渡到独立研究者所需的研究和专业技能。他的长期目标是开发一个成功的、独立的、校外资助的研究项目，利用转化方法（分子到人类）来研究内质网应激在代谢性疾病中的分子基础和临床意义。拟议的KO1奖将为Gentile博士实现这一目标提供必要的支持。

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.