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.

项目概要/摘要 当前的提案代表了以临床患者为导向和实验小鼠的结合 旨在研究肥胖症血管功能障碍机制的研究。 已发展成为我们最严重的医疗保健问题之一，因为目前 69% 的美国人口 超重或肥胖是必不可少的。 我们的初步数据将肥胖与心血管疾病的发病机制联系起来。 证明独特的促炎 Wnt 信号通路的显着上调，该通路可能发挥 在肥胖的血管功能障碍机制中的主要作用在本提案中，我们将研究其作用。 Wnt 信号在完整血管中微血管内皮功能调节中的作用 我们将利用多学科方法和从活体中获得的分离内皮细胞。 临床和基础科学家之间互补的专业知识来表征病理生理学 在目标 1 中，我们将描述功能失调的 Wnt5a 信号传导的特异机制。 使用视频显微镜观察人脂肪组织小动脉的血管内皮功能障碍 在选择性手术过程中从皮下和内脏脂肪室中分离出的血管 我们将在 150 名肥胖受试者和 50 名年龄和性别匹配的瘦受试者中描述血管特征。 与 Wnt 信号传导相关的表型并检验 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。 Wnt5a 和 TGFβ 途径的药理学和生物抑制剂将被使用 目标 1 中的小动脉和内皮细胞，以检验 Wnt5a 拮抗作用逆转的假设 血管功能障碍，部分是通过其调节脂肪组织中 EndoMT 的能力，并寻求 确定肥胖的新调节因子和治疗靶点以证实这些遗传发现。 模型中，我们将探索 EndoMT 以及小鼠的血管和代谢表型 目的 4：研究有条件地消除或过度表达骨髓细胞中的 Wnt5a。 挽救生命的减肥手术后 6 个月将重复进行内皮表型分析 对目标 1 中的 150 名肥胖受试者进行干预，以检查标记体重的影响 目标 2 和 3 中确定的小动脉反应和相关 Wnt 分子途径的减少。 整个项目结合了使用原发组织对细胞信号传导和全血管生理学的研究 来自目前临床上很少有血管数据的严重肥胖个体。 可能将 Wnt5a-Sfrp5 轴识别为血管生物学的新型调节剂，并可能导致 确定对抗肥胖引起的心血管疾病的新目标和方法。

项目成果

FSP27 and Links to Obesity and Diabetes Mellitus.

FSP27 以及与肥胖和糖尿病的联系。

• 发表时间: 2019-09
• 影响因子: 8.8
• 作者: Karki; Shakun
• 通讯作者: Shakun

Oxidative modifications of mitochondrial complex II are associated with insulin resistance of visceral fat in obesity.

线粒体复合物 II 的氧化修饰与肥胖内脏脂肪的胰岛素抵抗有关。

• DOI: 10.1152/ajpendo.00227.2018
• 发表时间: 2019-02-01
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: D. Ngo;A. Sverdlov;Shakun Karki;D. Macartney;R. Stubbs;M. Farb;Brian Carmine;D. Hess;W. Colucci;N. Gokce
• 通讯作者: N. Gokce