Anti-Angiogenic Mechanisms in Human Obesity

人类肥胖的抗血管生成机制

• 批准号: 8816544
• 负责人: NOYAN GOKCE
• 金额: $ 47.85万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-14 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816544
• 关键词: Adipose tissue; American; Angiogenesis Modulating Agents; Area; Bariatrics; Biological; Biology; Biopsy; Blood Vessels; Body Weight decreased; Body mass index; Cancer Biology; Cardiovascular Diseases; Cardiovascular system; Categories; Cause of Death; Cessation of life; Clinical; Data; Disease; Fatty acid glycerol esters; Functional disorder; Future; Generations; Guidelines; Health Care Costs; Healthcare; Homeostasis; Human; Human Cell Line; Hypoxia; Individual; Inflammation; Intervention; Knowledge; Laboratories; Lead; Link; Metabolic; Metabolic Diseases; Molecular; Morbid Obesity; Myocardial Ischemia; Obesity; Obesity associated cardiovascular disease; Operative Surgical Procedures; Overweight; Pathogenesis; Pathway interactions; Phenotype; Population; Prevalence; Process; Property; Protein Isoforms; RNA Splicing; Regulation; Research Priority; Role; Sampling; Scientist; Secure; Shapes; Signal Transduction; Stroke; System; Systemic disease; Techniques; Testing; Tissue Expansion; Tissue Sample; Variant; Vascular Diseases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vascularization; Visceral; Western Blotting; Work; angiogenesis; bariatric surgery; burden of illness; effective therapy; human VEGF protein; inhibitor/antagonist; macrophage; mortality; multidisciplinary; new therapeutic target; novel; premature; public health relevance; research study; response; weight loss intervention

DESCRIPTION (provided by applicant): Obesity has emerged as one of the most critical health care problems in the US as 69% of the US population is currently overweight or obese. Adipose tissue dysfunction is an essential hallmark linking obesity to the pathogenesis of cardiometabolic disease, and prior work form our group has demonstrated that qualitative properties of adipose tissue shape systemic phenotypes. In particular, impaired adipose tissue angiogenesis in obesity has been associated with inflammation and metabolic dysfunction; however pathogenic mechanisms are incompletely understood. We describe a novel endogenous isoform of vascular endothelial growth factor (VEGF-A), VEGF-A165b that is selectively over-expressed in obesity and inhibits angiogenesis. Our preliminary data suggest that perturbations in the Wnt5a signaling system up-regulates VEGF-A165b under conditions of obesity that is modified by bariatric surgical weight loss. In aim 1, we will examine adipose depot-specific microvascular angiogenic responses in biopsied fat samples from 150 obese and 50 lean subjects. We will characterize VEGF-A isoforms in relation to angiogenic capacity and vascularization. We hypothesize that inhibitory isoform VEGF-A165b will be up- regulated in obesity, associated with anti-angiogenic actions in fat, and relate to whole body metabolic dysfunction. In aim 2, specific inhibitors of Wnt signaling will be employed using human adipose tissue samples secured from aim 1 to provide a molecular framework for understanding the regulation of VEGF-A 165b expression. In aim 3, we will re-examine adipose angiogenic capacity and VEGF isoform expression at 6 months following bariatric surgery in the same 150 obese subjects from aim 1. We will test whether relevant molecular pathways specifically identified in aim 2 are influenced by weight reduction. We seek to identify novel determinants of adipose tissue biology and angiogenesis in relation to metabolic changes which will develop in association with marked weight loss in obese individuals. Our proposal may identify the Wnt5a-VEGF-A 165b axis as a novel modulator of angiogenesis, adipose tissue biology, and consequently, systemic disease in clinical obesity and potentially lead to the identification of new therapeutic targets.

描述（由申请人提供）：肥胖已成为美国最关键的医疗保健问题之一，目前有69%的美国人口超重或肥胖。脂肪组织功能障碍是将肥胖与心脏代谢疾病的发病机制联系起来的重要标志，我们小组先前的工作已经证明脂肪组织的定性特性决定了系统表型。特别是，肥胖的脂肪组织血管生成受损与炎症和代谢功能障碍有关；然而，致病机制尚不完全清楚。我们描述了一种新的内源性血管内皮生长因子（VEGF-A）， VEGF-A165b，在肥胖中选择性过表达并抑制血管生成。我们的初步数据表明，Wnt5a信号系统的扰动可以上调VEGF-A165b，而肥胖是通过减肥手术来改变的。在目的1中，我们将检查来自150名肥胖和50名瘦受试者的活检脂肪样本中脂肪库特异性微血管生成反应。我们将表征VEGF-A亚型与血管生成能力和血管化的关系。我们假设抑制异构体VEGF-A165b在肥胖中上调，与脂肪中的抗血管生成作用有关，并与全身代谢功能障碍有关。在目标2中，Wnt信号的特异性抑制剂将使用从目标1中获得的人类脂肪组织样本，为理解VEGF-A 165b表达的调控提供分子框架。在目标3中，我们将在目标1中相同的150名肥胖受试者中，在减肥手术后6个月重新检查脂肪血管生成能力和VEGF亚型表达。我们将测试目标2中明确的相关分子途径是否受到体重减轻的影响。我们试图确定脂肪组织生物学和血管生成的新决定因素，这些决定因素与代谢变化有关，这些变化将与肥胖个体的显著体重减轻有关。我们的建议可能会确定Wnt5a-VEGF-A 165b轴作为血管生成，脂肪组织生物学和临床肥胖全系统疾病的新调节剂，并可能导致新的治疗靶点的鉴定。