Identifying a novel regulatory pathway of vascular function in obesity

项目总结/摘要 目前的提议代表了一种结合临床的人类和实验动物模型 这项研究旨在研究肥胖相关的代谢和血管疾病机制。 肥胖已经发展成为我们最关键的医疗保健问题之一，69%的美国人口 目前超重或肥胖。脂肪组织功能障碍、脂毒性和胰岛素抵抗是 将肥胖与心血管疾病的发病机制联系起来的基本异常。这项建议会 采用一些互补的方法，利用血管的生理学研究， 内皮血管舒张功能和血管生成的活血管，创新的细胞自主增益和 功能丧失的生物学方法，和动物模型构建，以获得新的见解的作用， 新发现的FSP 27蛋白在血管疾病的发病机制。在目标1中，我们将调查 FSP 27在人脂肪组织小动脉功能障碍的储库特异性机制中的作用 微环境，使用视频显微镜和血管生成试验检查微血管反应 在选择性外科手术过程中活检的皮下和内脏脂肪隔室中， 在100名肥胖者和25名瘦人中。我们将检验FSP 27的下调与 胰岛素抵抗和血管功能障碍，并寻求FSP 27过表达的证据， 使用新的腺病毒方法逆转肥胖相关的血管功能障碍。在目标2中，我们将 探索FSP 27的作用机制，并确定定义内皮细胞的调节分子途径 通过在原代人细胞中进行细胞系特异性功能获得和丧失研究 源自目标1。我们还将试图描述脂肪细胞与 内皮细胞FSP 27表达在血管表型的控制，并将测试我们的假设， 脂肪-内皮串扰在血管功能障碍的调节中起关键作用。在目标3中，我们 将利用创新的小鼠模型，这些模型被工程化以过度表达内皮细胞和/或 脂肪细胞特异性的人FSP 27，以寻找FSP 27对血管内皮细胞的保护作用的证据。 功能障碍整个项目将使用两个实验室的主要优势与心血管（博士。 Gokce）和脂肪细胞生物学（Puri博士）的专业知识，并将联合收割机分子生物学与人类 在严重肥胖个体中的生理学，其中临床上目前存在非常少的血管数据。我们 该提案可能会解开沿着脂肪细胞-内皮轴的新途径，这些途径起着关键作用 血管生物学的调节剂，并可能导致新的药物靶标的鉴定， 逆转肥胖引起的心脏代谢疾病的方法。

Project Summary/Abstract The current proposal represents a combined clinical human and experimental animal model investigation which seeks to examine obesity-associated metabolic and vascular disease mechanisms. Obesity has developed into one of our most critical health care problems as 69% of the US population is currently overweight or obese. 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 in live vessels, innovative cell-autonomous gain-and- loss of function biological methods, and animal model constructs to gain novel insight into the role of a newly identified protein FSP27 in the pathogenesis of vascular disease. In aim 1, we will investigate the role of FSP27 in depot-specific mechanisms of arteriolar 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, in 100 obese and 25 lean subjects. We will test the hypothesis that down-regulation of FSP27 is linked to insulin resistance and vascular dysfunction, and also seek evidence that FSP27 overexpression using a novel adenoviral approach reverses obesity-related vascular dysfunction. In aim 2, we will probe mechanisms of FSP27 action and identify regulatory molecular pathways that define endothelial phenotypes by conducting cell-line specific gain-and-loss of function studies in primary human cells derived from aim 1. We will also seek to characterize the relative contribution of adipocyte vs. endothelial cell FSP27 expression in the control of vascular phenotype, and will test our hypothesis that adipose-endothelial cross-talk plays a crucial role in the regulation of vascular dysfunction. In aim 3, we will utilize innovative mouse models that are engineered to over-express endothelium- and/or adipocyte- specific human FSP27 to seek evidence for a protective effect of FSP27 against vascular dysfunction. The overall project will use major strengths of two laboratories with cardiovascular (Dr. Gokce) and adipocyte biology (Dr. Puri) expertise, and combine molecular biology with human physiology in severely obese individuals where clinically very little vascular data currently exist. Our proposal may unravel novel pathways along the adipocyte-endothelial axis that act as critical modulators of vascular biology and potentially lead to the identification of new drugable targets and approaches to reverse obesity-induced cardio-metabolic disease.