Role of T-Cadherin in Adiponection-mediated cardiovascular functions

T-钙粘蛋白在脂肪连接介导的心血管功能中的作用

• 批准号: 8055538
• 负责人: BARBARA RANSCHT
• 金额: $ 23.88万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-02 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055538
• 关键词: Address; Adipocytes; Adipose tissue; Age; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Binding Proteins; Binding Sites; Biochemical; Biology; Blood Circulation; Cadherins; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell surface; Cells; Coronary Arteriosclerosis; Defect; Docking; Drug Delivery Systems; Endothelial Cells; Epidemiologic Studies; Fatty acid glycerol esters; Functional disorder; Genes; Grant; H-Cadherin; Heart; Heart Diseases; Heart Hypertrophy; Human; Hypertension; Inflammatory; Knockout Mice; Laboratories; Lead; Ligand Binding; Link; Mediating; Membrane; Membrane Glycoproteins; Membrane Proteins; Metabolic; Metabolic Diseases; Metabolic syndrome; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Myocardial Infarction; Myocardial Ischemia; Obesity; Physiological; Recovery; Research; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Suggestion; Testing; Tissues; Vascular remodeling; Ventricular Remodeling; Wild Type Mouse; Work; adiponectin; base; cardiovascular injury; constriction; cytokine; genetic linkage; genetic linkage analysis; heart function; improved; in vivo; mouse model; mutant; novel; public health relevance; receptor; research study; response

DESCRIPTION (provided by applicant): Obesity-related metabolic syndrome is major risk factor for cardiovascular diseases. Adiponectin (APN), a circulating fat-secreted cytokine, is implicated in protecting against obesity-related metabolic and cardiovascular dysfunctions. Levels of APN decrease with the expansion of adipose tissue and low levels are associated with coronary artery disease, hypertension, heart infarct and other cardiovascular dysfunctions. In animal models of cardiac hypertrophy and ischemic heart disease, administration of APN improves pathological myocardial remodeling. While the beneficial functions of APN are well described, little is known about membrane receptors that enable APN's physiological functions in the cardiovascular system. T-cadherin, an APN binding protein implicated by genetic linkage analysis in cardiovascular functions, is a candidate cell surface glycoprotein to mediate APN functions. This R21 application will explore the functions of T-cadherin in a mouse model of heart disease and relate a potential role to the functions of adiponectin. PUBLIC HEALTH RELEVANCE: Obesity contributes to metabolic and cardiovascular disorders by altering the levels of adipocyte-secreted pro- and anti-inflammatory cytokines in the circulation. Adiponectin is a fat-secreted anti-inflammatory cytokine with beneficial actions in regulating metabolic and cardiovascular functions. Adiponectin associates with cardiomyocyte and endothelial cell surfaces to exert beneficial functions. The receptors that enable the engagement of adiponectin with cell surfaces and lead to activation of downstream signaling cascades remain poorly understood. Research proposed in this application will explore the contributions of T- cadherin, a novel adiponectin-binding cell surface glycoprotein, in functions of the heart and vasculature. Specifically, the proposed experiments will test if T-cadherin is essential for the cardioprotective actions of adiponectin. This work will contribute to understanding adiponectin's cardiovascular-protective functions and - if successful - form a new basis for exploring the T-cadherin-adiponectin interaction as a possible drug target for recovery from cardiovascular injury.

描述(申请人提供)：肥胖相关代谢综合征是心血管疾病的主要危险因素。脂联素(APN)是一种循环脂肪分泌的细胞因子，对肥胖相关的代谢和心血管功能障碍具有保护作用。APN水平随着脂肪组织的扩张而降低，低水平与冠状动脉疾病、高血压、心肌梗死等心血管功能障碍有关。在心肌肥厚和缺血性心脏病的动物模型中，应用APN可改善病理性心肌重塑。虽然APN的有益功能已被很好地描述，但对使APN在心血管系统中发挥生理功能的膜受体知之甚少。T-钙粘蛋白是一种APN结合蛋白，与心血管功能的遗传连锁分析有关，是介导APN功能的候选细胞表面糖蛋白。这项R21的应用将探索T-钙粘蛋白在心脏病小鼠模型中的功能，并与脂联素的功能相关。 公共卫生相关性：肥胖通过改变循环中脂肪细胞分泌的促炎和抗炎细胞因子水平而导致代谢和心血管疾病。脂联素是一种脂肪分泌的抗炎细胞因子，具有调节代谢和心血管功能的有益作用。脂联素与心肌细胞和内皮细胞表面结合，发挥有益的功能。能够使脂联素与细胞表面结合并导致下游信号级联激活的受体仍然知之甚少。在这项申请中提出的研究将探索T-钙粘蛋白，一种新的脂联素结合细胞表面糖蛋白，在心脏和血管系统功能中的作用。具体地说，拟议的实验将测试T-钙粘附素是否对脂联素的心脏保护作用是必要的。这项工作将有助于理解脂联素的心血管保护功能，如果成功，将为探索T-钙粘素-脂联素相互作用作为心血管损伤康复的可能药物靶点奠定新的基础。