Effects of Bariatric Surgery on HDL and Platelet Function

项目摘要/摘要 这项重新提交的研究将探索肥胖、高密度脂蛋白功能和血栓形成之间潜在的病理生理联系。 通过研究两种类型的减肥手术-Roux-en-Y胃分流术(RYGB)和袖状胃切除术 (SG)-影响(1)病态肥胖者的血小板功能和基因表达，以及(2)体外效应 高密度脂蛋白对血小板聚集和血小板前体基因表达的影响。它还将检查高密度脂蛋白的变化。 RYGB和SG对肥胖患者高密度脂蛋白功能影响的不同机制。 应聘者：这份申请将支持肖恩·赫夫龙博士的职业发展 翻译心血管(CV)医生-肥胖和心血管疾病(CVD)领域的科学家。 赫夫龙博士的职业目标是更好地了解肥胖如何增加心血管疾病风险，以及心血管疾病风险是如何 调制不同的减肥技术，支持开发有效的治疗方法来缓解 这种风险。他提出的培训计划集中在3个领域：(1)转化型实验室技术；(2)研究 方法与设计；(3)统计分析与生物医学信息学。环境：纽约大学医学院 是全国研究领域的领先者，也是NIH资助的前20所医学院之一。分部 心脏病学是全国排名第一的部门，在纽约大学医学院拥有最大的研究预算 医学。研究：近9000万美国人肥胖，动脉粥样硬化风险增加 血栓形成和心血管病死率。肥胖患者的高密度脂蛋白功能受损可能是导致这种风险增加的原因之一。Dr。 Heffron的初步数据表明，SG后，高密度脂蛋白在胆固醇外流中的功能增加，但减少 跟随RYGB。一些体外和动物数据表明，高密度脂蛋白外流可能调节血小板功能 并降低血栓形成的风险。目前尚不清楚SG和RYGB是否通过作用于 胆固醇外流。这一知识将建议潜在的机制，可以评估干预 降低肥胖和非肥胖人群的心血管和血栓风险。为了研究SG的作用和 RYGB对血小板特性和功能的影响，特别是对减肥手术后高密度脂蛋白的测量 血小板活性，这个项目将包括对保存的生物标本的分析和未来的 肥胖症患者接受减肥手术的疗效对比研究 RYGB对高密度脂蛋白介导的胆固醇外流对血小板功能和基因表达的影响。具体目标 目的是：(1)确定RYGB和SG对高密度脂蛋白功能的不同影响的潜在机制；(2)确定 如果减肥手术提高了高密度脂蛋白抑制血小板活化和巨核细胞炎症的能力 状态，以及(3)确定手术减肥是否导致重症患者的血小板炎症和活化减少 肥胖。通过使用多种方法探索肥胖与高密度脂蛋白之间潜在的病理生理联系 功能和血栓形成，这些创新的研究将支持在翻译研究中强有力的培训计划 肥胖症和心血管疾病，并促进PI发展成为独立的翻译医生-科学家。

Project Summary/Abstract This resubmission will explore a potential pathophysiologic link between obesity, HDL function and thrombosis by examining how two types of bariatric surgery – Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) – affect (1) platelet function and gene expression in morbidly obese individuals, and (2) the in vitro effect of HDL on platelet aggregation and platelet precursor gene expression. It will also examine changes in HDL composition as mechanisms underlying the differential effects of RYGB and SG on HDL function in obesity. Candidate: This application will support Dr. Sean Heffron's career development into an independent translational cardiovascular (CV) physician-scientist in the field of obesity and cardiovascular disease (CVD). Dr. Heffron's career goal is to better understand how obesity elevates CVD risk, and how CVD risk is modulated by different weight loss techniques, to support the development of effective therapies to alleviate this risk. His proposed training plan focuses on 3 areas: (1) translational laboratory techniques; (2) research methods & design; and (3) statistical analysis & biomedical informatics. Environment: NYU School of Medicine is a national leader in research and one of the top 20 medical schools in NIH funding. The Division of Cardiology is a top-ranked division nationally, with the largest research budget in the NYU Department of Medicine. Research: Nearly 90 million Americans are obese and at increased risk for atherosclerosis, thrombosis and CV mortality. Impaired HDL function in obesity may contribute to this increased risk. Dr. Heffron's preliminary data indicate that HDL function in cholesterol efflux increases after SG, but decreases following RYGB. Some in vitro and animal data suggest HDL cholesterol efflux may regulate platelet function and reduce the risk of thrombosis. It is unclear whether SG and RYGB affect platelets via their effects on cholesterol efflux. This knowledge will suggest potential mechanisms that may be assessed for intervention to reduce CV and thrombosis risk in both obese and non-obese individuals. To investigate the effect of SG and RYGB on platelet characteristics and function, and specifically post-bariatric surgery HDL on measures of platelet activity, this project will include both analysis of preserved biospecimens and a prospective study of obese patients undergoing bariatric surgery to thoroughly compare the effects of SG and RYGB on HDL-mediated cholesterol efflux in platelet function and gene expression. The specific aims are to: (1) identify mechanisms underlying differential effects of RYGB and SG on HDL function, (2) determine if bariatric surgery improves the ability of HDL to inhibit platelet activation and megakaryocyte inflammatory state, and (3) determine if surgical weight loss results in reduced platelet inflammation and activation in severe obesity. By using multiple approaches to explore a potential pathophysiologic link between obesity, HDL function, and thrombosis, these innovative studies will support a robust training plan in translational research in obesity and CVD, and promote the development of the PI into an independent translational physician-scientist.