Effects of Bariatric Surgery on HDL and Platelet Function

减肥手术对高密度脂蛋白和血小板功能的影响

• 批准号: 10207741
• 负责人: Sean Patrick Heffron
• 金额: $ 4.81万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207741
• 关键词: Affect; American; Area; Atherosclerosis; Bariatrics; Blood Platelets; Blood coagulation; Body Weight decreased; Body mass index; Budgets; Cardiology; Cardiovascular Diseases; Cardiovascular system; Characteristics; Cholesterol; Clinical Research; Data; Development; Environment; Event; Exhibits; Exposure to; Foundations; Functional disorder; Funding; Future; Gastrectomy; Gastric Bypass; Gene Activation; Gene Expression; Genes; Goals; Gold; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Impairment; In Vitro; Inflammation; Inflammatory; Intervention; Knowledge; Laboratories; Link; Lipids; Measures; Mediating; Mediator of activation protein; Medicine; Megakaryocytes; Membrane; Meta-Analysis; Metabolic; Methods; Modification; Morbid Obesity; Mus; Non obese; Obesity; Operative Surgical Procedures; Outcome; Phospholipids; Physicians; Plasma; Platelet Activation; Platelet aggregation; Procedures; Property; Prospective Studies; Research; Research Design; Research Methodology; Risk; Risk Factors; Role; S100A9 gene; Sampling; Scientist; Serum; Statistical Data Interpretation; Techniques; Testing; Thrombosis; Training; Transcript; Translational Research; United States National Institutes of Health; Variant; Woman; Work; animal data; atherosclerosis risk; bariatric surgery; base; biomedical informatics; cardioprotection; cardiovascular disorder risk; cardiovascular risk factor; career; career development; effective therapy; experience; experimental study; improved; innovation; insight; macrophage; medical schools; mortality; novel marker; obese patients; obese person; particle; platelet function; preservation; prospective; thrombogenesis; thrombotic; translational physician; translational scientist; translational study

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.

项目概要/摘要 本次重新提交将探讨肥胖、HDL 功能和血栓形成之间潜在的病理生理联系 通过检查两种类型的减肥手术——Roux-en-Y胃绕道手术（RYGB）和袖状胃切除术的效果 (SG) – 影响 (1) 病态肥胖个体的血小板功能和基因表达，以及 (2) 体外效应 HDL 对血小板聚集和血小板前体基因表达的影响。它还将检查 HDL 的变化 RYGB 和 SG 对肥胖 HDL 功能差异影响的机制。 候选人：该申请将支持 Sean Heffron 博士的职业发展成为独立的 肥胖和心血管疾病（CVD）领域的转化心血管（CV）医师科学家。 Heffron 博士的职业目标是更好地了解肥胖如何增加 CVD 风险，以及 CVD 风险如何影响 通过不同的减肥技术进行调节，以支持开发有效的疗法来缓解 这种风险。他提出的培训计划重点关注三个领域：（1）转化实验室技术； (二)研究 方法与设计； (3)统计分析和生物医学信息学。环境：纽约大学医学院 是研究领域的全国领先者，也是 NIH 资助最多的 20 所医学院之一。分部 心脏病学是全美排名第一的科室，纽约大学心脏病学系的研究预算最多 药品。研究：近 9000 万美国人肥胖，动脉粥样硬化的风险增加， 血栓形成和心血管死亡率。肥胖导致的高密度脂蛋白功能受损可能会导致这种风险增加。博士。 Heffron的初步数据表明，SG后HDL在胆固醇流出中的功能增加，但降低 遵循 RYGB。一些体外和动物数据表明 HDL 胆固醇流出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 是否通过影响血小板来影响血小板 胆固醇外流。这些知识将提出可评估干预措施的潜在机制 降低肥胖和非肥胖个体的心血管和血栓形成风险。研究 SG 和 RYGB 对血小板特征和功能的影响，特别是减肥手术后 HDL 对血小板特征和功能的影响 血小板活性，该项目将包括对保存的生物样本的分析和前瞻性研究 对接受减肥手术的肥胖患者进行的研究，以彻底比较 SG 和 RYGB 对 HDL 介导的胆固醇流出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 HDL 功能差异影响的机制，(2) 确定 减肥手术能否提高HDL抑制血小板活化和巨核细胞炎症的能力 状态，以及（3）确定手术减肥是否会导致严重情况下血小板炎症和激活的减少 肥胖。通过使用多种方法探索肥胖、HDL 之间潜在的病理生理联系 功能和血栓形成，这些创新研究将支持转化研究的稳健培训计划 肥胖和心血管疾病，并促进 PI 发展成为独立的转化型医师科学家。