FSP27 regulation of vascular function in human obesity

FSP27 对人类肥胖血管功能的调节

• 批准号: 10433502
• 负责人: Shakun Karki
• 金额: $ 6.74万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 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/10433502
• 关键词: Adipose tissue; Age; American; Area; Bariatrics; Biological; Biology; Blood Vessels; Body Weight decreased; Cardiovascular Diseases; Clinical; Data; Elective Surgical Procedures; Endothelial Cells; Endothelium; Engineering; Functional disorder; Gender; Genetic Models; Healthcare; Human; Inflammation; Inflammatory; Insulin Resistance; Investigation; Lead; Life; Link; Mediating; Metabolic Diseases; Molecular; Morbid Obesity; Mus; Myeloid Cells; Obesity; Operative Surgical Procedures; Overweight; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Physiology; Play; Population; Public Health; Regulation; Role; Savings; Scientist; Signal Transduction; Testing; Thinness; Tissues; Transforming Growth Factor beta; Up-Regulation; Vascular Diseases; Video Microscopy; Visceral fat; WNT Signaling Pathway; arteriole; combat; inhibitor/antagonist; interdisciplinary approach; metabolic phenotype; mortality; novel; obese person; overexpression; patient oriented; response; subcutaneous; therapeutic target; vascular endothelial dysfunction

Project Summary/Abstract The current proposal represents a combined clinical patient-oriented and experimental murine investigation which seeks to examine mechanisms of vascular dysfunction in obesity. 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, inflammation, and insulin resistance are essential hallmarks linking obesity to the pathogenesis of cardiovascular disease. Our preliminary data demonstrate marked up-regulation of a unique pro-inflammatory Wnt signaling pathway that may play a major role in mechanisms of vascular dysfunction in obesity. In this proposal, we will examine the role of Wnt signaling in the regulation of microvascular endothelial function in intact blood vessels and isolated endothelial cells acquired from living subjects. We will utilize a multidisciplinary approach and complementary expertise between clinical and basic scientists to characterize the pathophysiological role of dysfunctional Wnt5a signaling. In aim 1, we will characterize depot-specific mechanisms of vascular endothelial dysfunction in human adipose tissue arterioles using videomicroscopy of small vessels isolated from subcutaneous and visceral fat compartments during elective surgical procedures in 150 obese and 50 age- and gender-matched lean subjects. We will characterize vascular phenotypes in relation to Wnt signaling and test the hypothesis that over-activation of Wnt5a-mediated signaling is a dominant regulatory feature that leads to vascular dysfunction. In aims 2 and 3, specific pharmacological and biological inhibitors of the Wnt5a and TGFβ pathways will be employed using arterioles and endothelial cells from aim 1 to test the hypothesis that antagonism of Wnt5a reverses vascular dysfunction, in part through its ability to modulate EndoMT in adipose tissue, and seek to identify novel regulators and therapeutic targets in obesity. To corroborate these findings in genetic models, we will explore EndoMT and the vascular and metabolic phenotypes of mice that are engineered to conditionally ablate or overexpress Wnt5a in myeloid cells. In aim 4, studies of endothelial phenotyping will be repeated 6-months after life-saving bariatric weight loss surgical intervention in the same 150 obese subjects from aim 1 to examine the effects of marked weight reduction on arteriolar responses and relevant Wnt molecular pathways identified in aims 2 and 3. The overall project combines studies of cellular signaling and whole vessel physiology using primary tissues from severely obese individuals where clinically very little vascular data currently exist. Our proposal may identify the Wnt5a-Sfrp5 axis as a novel modulator of vascular biology and potentially lead to the identification of new targets and approaches to combat obesity-induced cardiovascular disease.

项目摘要/摘要 当前的建议代表了临床以患者为导向和实验性鼠的组合 旨在检查肥胖症血管功能障碍机制的研究。肥胖有 发展成为我们最关键的医疗保健问题之一，因为目前有69％的美国人口 超重或肥胖。脂肪组织功能障碍，感染和胰岛素抵抗是必不可少的 将肥胖与心血管疾病的发病机理联系起来的标志。我们的初步数据 证明了可能发挥的独特促炎Wnt信号通路的明显上调 在肥胖症中血管功能障碍机制中的主要作用。在此提案中，我们将研究角色 在完整血管中的微血管内皮功能调节中，Wnt信号传导的 从活物受试者获得的分离的内皮细胞。我们将利用一种多学科的方法， 临床和基本科学家之间的完全专业知识，以表征病理生理学 功能失调的WNT5A信号传导的作用。在AIM 1中，我们将表征特定存款的机制 人脂肪组织动脉中的血管内皮功能障碍使用小型视频显微镜检查 在选修手术过程中，从皮下和内脏脂肪室分离的血管 在150名肥胖和50岁和性别匹配的精益科目中。我们将表征血管 与Wnt信号传导有关的表型，并检验了Wnt5a介导的过度激活的假设 信号传导是导致血管功能障碍的主要调节特征。在目标2和3中，具体 WNT5A和TGFβ途径的药理和生物学抑制剂将使用 AIM 1的小动脉和内皮细胞测试了Wnt5a拮抗作用的假设 血管功能障碍，部分是通过调节脂肪组织内植物的能力，并寻求 确定肥胖症中新型调节剂和治疗靶标。为了证实遗传中的这些发现 模型，我们将探索小鼠的胚胎和血管和代谢表型 设计为有条件地在髓样细胞中烘烤或过表达Wnt5a。在AIM 4中，研究 挽救生命减肥手术后，内皮表型将重复6个月 对AIM 1的同一150名肥胖受试者进行干预，以检查明显重量的影响 在目标2和3中鉴定的小动脉反应和相关的Wnt分子途径的减少。 总体项目组合研究细胞信号传导和整个血管生理的研究 从目前存在临床上很少有血管数据的严重肥胖个体。我们的建议 可以将WNT5A-SFRP5轴确定为血管生物学的新调节剂，并有可能导致 确定对抗肥胖引起的心血管疾病的新目标和方法。