FSP27 regulation of vascular function in human obesity

FSP27 对人类肥胖血管功能的调节

基本信息

批准号：
10183236
负责人：
Shakun Karki
金额：
$ 13.47万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183236
关键词：
Adipocytes Adipose tissue Advisory Committees American Area Atherosclerosis Bariatrics Biological Biological Assay Biology Biopsy Blood Vessels Body Weight decreased Cardiovascular Diseases Cardiovascular system Clinical Clinical Data Coronary Arteriosclerosis Data Disease Resistance Down-Regulation Elective Surgical Procedures Endothelium Endothelium-Dependent Relaxing Factors Fatty acid glycerol esters Functional disorder Gap Junctions Goals Healthcare Human Immunohistochemistry Impairment Inflammation Insulin Insulin Resistance Intervention Investigation Knowledge Link Lipolysis Mass Spectrum Analysis Medical Mentored Research Scientist Development Award Mentors Metabolic Methods Molecular Molecular Biology Morbid Obesity Nitric Oxide Synthase Obesity Obesity associated cardiovascular disease Operative Surgical Procedures Overweight Pathogenesis Pathogenicity Pathway interactions Pharmacology Phenotype Physiological Physiology Population Process Proteins Proteomics Public Health Regulation Reverse Transcriptase Polymerase Chain Reaction Risk Reduction Role Signal Pathway Signal Transduction Surveys Systems Biology Testing Thinness Tissues Training Training Programs Translational Research Vascular Diseases Vascular Endothelial Cell Vascular Endothelium Vasodilator Agents Video Microscopy Visceral Visceral fat Western Blotting angiogenesis arteriole bariatric surgery base cardiometabolic risk career career development clinically significant experimental study extracellular human subject improved insight insulin sensitivity insulin signaling interest member metabolic phenotype mortality novel obese person patient oriented preservation response skills subcutaneous vasoconstriction weight loss intervention

项目摘要

Project Summary/Abstract This proposal describes a 5-year training program that will expand the applicant's scientific knowledge, advance her expertise in patient-oriented translational research, and establish independence from her primary mentor. A 4-member Mentoring Team and 3-member Advisory Committee will oversee her training and career development. The current application represents a patient-oriented clinical proposal that examines mechanisms of obesity-associated vascular disease in human subjects. Adipose tissue dysfunction, lipotoxicity, and insulin resistance are essential abnormalities linking obesity to the pathogenesis of cardiovascular disease. This proposal will employ a number of complementary approaches harnessing physiological studies of vascular endothelial vasodilator function and angiogenesis, pharmacological and biological methods to probe dysfunctional signaling pathways, and proteomics-based approaches to gain novel insight into the role of a newly identified protein FSP27 in the pathogenesis of vascular disease in obesity. In aim1, we will investigate the role of FSP27 in depot- specific mechanisms of vascular dysfunction in the human adipose tissue microenvironment, using videomicroscopy and angiogenic assays to examine microvascular responses in both subcutaneous and visceral adipose compartments biopsied during elective surgical procedures, including bariatric surgery, in 150 obese and 50 lean subjects. We will characterize vascular phenotypes in relation to FSP27 signaling and test the hypothesis that down-regulation of FSP27 is linked to insulin resistance and vascular dysfunction. In aim 2, we will seek to identify molecular mechanisms that contribute to FSP27 regulation of vascular function by employing proteomics-based approaches using mass spectrometry to identify proteins and subsequent pathways differentially modulated by FSP27 in relevance to lipotoxicity, insulin resistance, and vascular biology. In aim 3, vascular studies, metabolic phenotyping, and proteomics will be repeated at 6-months following bariatric surgical intervention in the same 150 obese subjects from aims 1 and 2. We will test whether relevant FSP27-related molecular pathways identified in aim 2 are influenced by marked weight loss and/or metabolic changes and hypothesize that weight loss will improve vascular phenotype and linked to FSP27 signaling. The overall project will combine molecular biology with human physiology in severely obese individuals where clinically very little vascular data currently exist. The long-term goal of the applicant is to develop an academic career in the field of obesity and cardiovascular disease, and this proposal will allow the applicant to expand her translational expertise in an area that is relatively unexplored and medically important. Obesity will remain one of the most important health care challenges worldwide, and improving our understanding of mechanisms of obesity-related cardiovascular disease is critical.

项目概要/摘要该提案描述了一个为期 5 年的培训计划，该计划将扩展申请人的科学知识，提高她在以患者为导向的转化研究方面的专业知识，并建立独立于她的地位主要导师。一个由 4 名成员组成的指导团队和 3 名成员组成的咨询委员会将监督她培训和职业发展。当前的应用代表了以患者为中心的临床建议研究人类受试者肥胖相关血管疾病的机制。脂肪组织功能障碍、脂毒性和胰岛素抵抗是与肥胖相关的重要异常。心血管疾病的发病机制。该提案将采用一些互补的利用血管内皮血管舒张功能的生理学研究的方法和血管生成、药理学和生物学方法来探测功能失调的信号通路，以及基于蛋白质组学的方法获得新发现的蛋白质 FSP27 在肥胖症血管疾病的发病机制。在目标1中，我们将研究FSP27在仓库中的作用人类脂肪组织微环境中血管功能障碍的具体机制，使用视频显微镜和血管生成测定来检查皮下的微血管反应在选择性外科手术（包括减肥手术）期间对内脏脂肪室进行活检对 150 名肥胖受试者和 50 名瘦受试者进行了手术。我们将描述与以下相关的血管表型 FSP27 信号传导并测试 FSP27 下调与胰岛素抵抗相关的假设和血管功能障碍。在目标 2 中，我们将寻求确定有助于 FSP27 通过采用基于蛋白质组学的质量方法来调节血管功能光谱法鉴定 FSP27 差异调节的蛋白质和后续通路与脂毒性、胰岛素抵抗和血管生物学的相关性。目标 3、血管研究、代谢表型分析和蛋白质组学将在减肥手术干预后 6 个月重复进行与目标 1 和 2 相同的 150 名肥胖受试者。我们将测试相关的 FSP27 相关分子是否目标 2 中确定的途径受到显着的体重减轻和/或代谢变化的影响，并且假设减肥将改善血管表型并与 FSP27 信号传导有关。这整个项目将把分子生物学与人类生理学结合起来，研究严重肥胖的个体目前临床上存在的血管数据非常少。申请人的长期目标是发展肥胖和心血管疾病领域的学术生涯，该提案将使申请人在相对未开发的医学领域扩展其翻译专业知识重要的。肥胖仍将是全球最重要的卫生保健挑战之一，并且提高我们对肥胖相关心血管疾病机制的理解至关重要。