Role of Endoplasmic Reticulum Stress in Obesity-Related Endothelial Dysfunction

描述（由申请人提供）：候选人：候选人，克里斯托弗L。Gentile博士，是科罗拉多州立大学人类营养和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，最近，在内皮功能障碍的发展中。他的近期目标是继续他的博士后培训，以获得必要的研究和专业技能，成功地过渡到一个独立的调查。他的长期目标是开发一个成功的独立的，壁外资助的研究计划，利用翻译方法（分子到人类）来研究ER应激在代谢疾病中的分子基础和临床意义。拟议的KO 1奖将为Gentile博士实现这一目标提供必要的支持。 职业发展：Gentile博士在本申请中的职业发展培训包括：1）获得与拟议研究计划相关并对其进行补充的新研究技能;以及2）结构化活动，包括正式的课程工作，每周期刊俱乐部，大学研讨会系列和科学会议的出席和演讲，以及与他的指导团队的定期互动。 环境：詹蒂莱博士的培训计划的环境将是杰出的。主要导师Pagliassotti博士和共同导师Seals博士都是国际公认的、由校外资助的科学家，在与代谢疾病有关的生物医学研究方面有着成功的指导记录。他们由一群杰出的咨询导师组成，由知名的研究人员组成，每个人都在Gentile博士的研究项目和整体培训计划的关键领域提供特定的专业知识。 研究：内皮功能障碍是2型糖尿病和心血管疾病的独立危险因素。该研究项目的总体目标是测试新的假设，即ER应激在与代谢疾病和脂质异常相关的内皮功能障碍的发展中起作用。拟议的研究将利用一种翻译方法（分子到人类）来研究这个问题。目的1将研究饱和脂肪酸诱导培养的人内皮细胞内质网应激的机制，并确定内质网应激是否直接介导内皮细胞功能障碍和死亡。目的2将检查高饱和脂肪饮食是否诱导雄性Wistar大鼠血管中的ER应激，如果是的话，这种ER应激是否介导由这种饮食引起的内皮功能障碍。目的3将检查肥胖个体中是否存在血管ER应激，以及高饱和脂肪餐是否诱导瘦个体中的血管ER应激并导致肥胖个体中的进一步升高。总的来说，这些研究可以确定一个新的机制，内皮功能障碍的发展。该提案中采用的独特翻译方法将使Gentile博士能够同时探索ER应激和内皮功能障碍之间的分子联系，并确定这种联系的临床意义。

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.