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

 描述（由申请人提供）：这个NRSA个人博士后奖学金的目标是促进Sadiya Khan博士作为独立的医生科学家和转化心脏代谢研究的领导者的发展，重点是肥胖和肥胖相关疾病的分子机制。Khan博士和她的导师设计了一个具体的培训计划，以建立她在内科，临床心脏病学培训以及基础和临床研究方面的背景，旨在启动她作为独立研究者的职业生涯。Khan博士建议在获奖期间通过（1）旨在扩大她的方法学技能的课程来发展其他技能;（2）与赞助商和合作者的多学科团队互动，包括血管生物学和心血管和遗传流行病学，以及（3）监督研究项目。本项目的总体科学目标是通过两个主要的具体目标来研究纤溶酶原激活物抑制剂-1（派- 1）（一种丝氨酸蛋白酶抑制剂）在体重增加和肥胖中的作用：（1）在年轻成人冠状动脉疾病风险（CARDIA）研究中确定从早期成年到中年的循环派-1水平的纵向分布并研究其与肥胖的关联;和（2）描述Berne Amish家族中独特的人派-1功能丧失队列的人体测量和代谢表型。该项目，沿着拟议的课程和导师计划，将使候选人成为精通翻译研究方法，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。该项目将满足美国国立卫生研究院的使命，通过合作研究基础设施，实现有关肥胖原因的基本发现的转化，其总体目标是帮助减少肥胖和肥胖相关疾病的重大公共卫生负担。需要提高对肥胖症发生、发展和并发症的分子机制的理解，以开发新的潜在治疗靶点，并帮助进行原始和一级预防。在奖励期结束时，Khan博士计划提交一份独立奖申请或类似的赠款，利用该项目的结果进一步研究肥胖和心脏代谢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.