FSP27 regulation of vascular function in human obesity

项目总结/摘要 该提案描述了一个为期5年的培训计划，将扩大申请人的科学知识， 提升她在以患者为导向的转化研究方面的专业知识，并建立独立于她的能力。 第一导师一个由4名成员组成的指导小组和3名成员组成的咨询委员会将监督她 培训和职业发展。目前的申请代表了以患者为导向的临床建议 研究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将肥胖与糖尿病联系起来的重要异常。 心血管疾病的发病机制。该提案将采用一些补充性的 利用血管内皮血管舒张功能的生理学研究的方法， 血管生成，药理学和生物学方法来探测功能失调的信号传导途径，和 基于蛋白质组学的方法，以获得新的见解的作用，一个新发现的蛋白FSP 27在 肥胖症血管疾病的发病机制。在aim 1中，我们将研究FSP 27在储库中的作用- 在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，以检查两个皮下组织中的微血管反应 和在选择性外科手术（包括减肥手术）期间对内脏脂肪室进行活检 手术，在150肥胖和50瘦受试者。我们将描述血管表型与 FSP 27信号传导，并检验FSP 27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 FSP 27通过采用基于蛋白质组学的方法使用质量调节血管功能 光谱法鉴定蛋白质和随后的途径差异调节FSP 27在 与脂毒性、胰岛素抵抗和血管生物学相关。在目标3中，血管研究、代谢 表型分析和蛋白质组学将在肥胖手术干预后6个月重复进行， 目标1和目标2中相同的150名肥胖受试者。我们将检测相关的FSP 27相关分子 目标2中确定的途径受到显著的体重减轻和/或代谢变化的影响， 假设体重减轻将改善血管表型并与FSP 27信号传导有关。的 整个项目将联合收割机结合分子生物学与人体生理学在严重肥胖的个人 其中临床上目前存在非常少的血管数据。申请人的长期目标是发展 在肥胖和心血管疾病领域的学术生涯，这一建议将允许 申请人在一个相对未开发和医学领域扩展她的翻译专业知识 重要.肥胖仍将是全球最重要的卫生保健挑战之一， 提高我们对肥胖相关心血管疾病机制的理解至关重要。

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.