The Role of Plasminogen Activator Inhibitor-1 in the Development and Progression of Obesity

 描述(由申请者提供)：NRSA个人博士后奖学金的目标是促进Sadiya Khan博士成为一名独立的内科科学家和翻译心脏代谢研究的领导者，重点关注肥胖和肥胖相关疾病的分子机制。Khan博士和她的导师们设计了一个具体的培训计划，以她在内科、临床心脏病学培训以及基础和临床调查方面的背景为基础，旨在开启她作为一名独立调查员的职业生涯。汗博士建议在获奖期间通过(1)旨在扩展她的方法技能的课程作业；(2)与赞助商和合作者组成的多学科团队进行互动，包括血管生物学、心血管和遗传流行病学方面的团队，以及(3)一个受监督的研究项目，来发展更多的技能。该项目的总体科学目标是通过两个主要的特定目标来研究纤溶酶原激活物抑制物-1(PAI-1)，一种丝氨酸蛋白酶抑制物，在体重增加和肥胖中的作用：(1)确定从成年早期到中年循环中PAI-1水平的纵向分布，并研究与肥胖在青年冠状动脉疾病风险(CARDIA)研究中的关系；(2)表征伯尔尼阿米什家族中一个独特的人类PAI-1功能丧失队列的人体测量和代谢表型。该项目与拟议的课程和指导计划一起，将使候选人精通翻译研究方法，特别强调纵向队列研究、数据分析和管理、遗传流行病学和科学写作。该项目将实现美国国立卫生研究院的使命，通过一个合作的研究基础设施，实现对肥胖原因的基本发现的转化，总体目标是帮助减轻肥胖和肥胖相关疾病带来的重大公共健康负担。需要加强对肥胖症发生、发展和并发症的分子机制的了解，以开发新的潜在治疗靶点，并帮助原始和初级预防努力。在获奖期接近尾声时，可汗博士计划利用该项目的结果提交一份《走向独立之路》的申请或类似的拨款，以进一步研究肥胖和心脏代谢性疾病结局之间的分子机制。

 DESCRIPTION (provided by applicant): The goal of this NRSA individual postdoctoral fellowship is to facilitate Dr. Sadiya Khan's development as an independent physician-scientist and a leader in translational cardiometabolic research, with a focus on molecular mechanisms of obesity and obesity-related diseases. Dr. Khan and her mentors have designed a specific training plan to build upon her background in internal medicine, clinical cardiology training, and basic and clinical investigation, aiming towards launching her career as an independent investigator. Dr. Khan proposes to develop additional skills during the award period through (1) coursework designed to expand her methodological skills; (2) interaction with a multidisciplinary team of sponsors and collaborators, including those in vascular biology and cardiovascular and genetic epidemiology, and (3) a supervised research project. The overall scientific objective of this project is to investigate the role of plasminogen activator inhibitor-1 (PAI- 1), a serine protease inhibitor, in weight gain and obesity through two primary specific aims: (1) To define the longitudinal profile of circulating PAI-1 levels across early adulthood to middle-age and investigate the association with obesity in the Coronary Artery Disease Risk in Young Adults (CARDIA) study; and (2) To characterize the anthropometric and metabolic phenotype of a unique human PAI-1 loss-of-function cohort in the Berne Amish kindred. The project, along with the proposed coursework and mentorship plan, will allow the candidate to become proficient at translational research methodology with a special emphasis on longitudinal cohort studies, data analysis and management, genetic epidemiology, and scientific writing. This project will meet the mission of the National Institutes of Health by enabling the translation of basic discoveries about the causes of obesity through a collaborative research infrastructure with an overarching goal to help reduce the significant public health burden of obesity and obesity-related diseases. Improving the understanding of the molecular mechanisms underlying the development, progression, and complications of obesity is needed to develop new potential targets for treatment and to aid in primordial and primary prevention efforts. Near the end of the award period, Dr. Khan plans to submit a pathway to independence award application or similar grant using the results of the project to further investigate the molecular mechanisms linking obesity and cardiometabolic disease outcomes.