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

候选人：克里斯托弗·L·真蒂尔，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。詹蒂勒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，以便获得成功过渡到独立调查人员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、由外部资助的研究计划，利用翻译方法(分子到人类)来研究代谢疾病中内质网应激的分子基础和临床意义。拟议的KO1奖将为詹蒂勒博士提供必要的支持，以实现这一目标。 职业发展计划：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和补充的新研究技能；2)有组织的活动，包括正式课程工作、出席每周期刊俱乐部、大学系列研讨会和科学会议并发表演讲，以及与他的指导团队的定期互动。 环境：詹蒂尔博士的培训计划所需的环境将非常出色。主要导师Pagliassotti博士和共同导师Seals博士都是国际公认的、由外部资助的科学家，在与代谢性疾病有关的生物医学研究方面有着成功的指导记录。他们还拥有一支由知名研究人员组成的杰出的咨询导师团队，每个人都在詹蒂尔博士的研究项目和整体培训计划的一个关键领域提供具体的专业知识。 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检验这一新的假设，即内质网应激在与代谢性疾病和血脂异常相关的内皮功能障碍的发展中发挥作用。这项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大鼠血管系统的内质网应激，如果是，这种内质网应激是否介导了这种饮食导致的内皮功能障碍。目标3将检查肥胖个体中是否存在血管内质网应激，以及高饱和脂肪餐是否会在瘦个体中诱导血管内质网应激，并导致肥胖者进一步升高。总而言之，这些研究可以确定内皮功能障碍发生的新机制。这项建议中采用的独特的翻译方法将使詹蒂尔博士能够同时探索内质网应激与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.