Adiponectin in Cardiovascular Biology and Pathology

脂联素在心血管生物学和病理学中的作用

• 批准号: 7217666
• 负责人: Harvey F Lodish
• 金额: $ 45.73万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217666
• 关键词: adipocytes; adiponectin; atherosclerosis; biological signal transduction; blood vessels; cadherins; coronary disorder; cyclic AMP; genetically modified animals; glucose metabolism; laboratory mouse; metabolism; nitric oxide; nuclear factor kappa beta; protein isoforms; protein kinase; protein structure function; receptor; transfection /expression vector; vascular endothelium; vascular smooth muscle

Our overall goal to understand the role of the adipokine adiponectin in vascular function, atherosclerosis, and coronary heart disease. Adiponectin is produced exclusively by adipocytes and is found at high levels in the intima surrounding several types of blood vessels. Adiponectin plays a key role in regulating hepatic and muscle fat and glucose metabolism and also the metabolism and proliferation of vascular smooth muscle and possibly endothelial cells. We identified several adiponectin orthologs, expressed mainly by adipocytes that share biological activities and signaling properties with adiponectin; these, like adiponectin, may regulate metabolism of vascular cells. The identities of the adiponectin signaling receptors and signal transduction pathways are not known; our and other labs have unequivocally shown that previously reported, putative signaling receptors for adiponectin do not function in that capacity. We identified T-cadherin, a GPI- anchored surface protein, as an adiponectin binding protein that is highly and specifically expressed by cells in the blood vessel intima. Deletion of T-cadherin in mice results in a decrease in adiponectin in the vasculature and a major increase in the circulation, indicating it is a major adiponectin receptor. However, additional cell surface receptors are necessary to mediate adiponectin signaling. We will clone these signaling adiponectin receptors, analyze their structures and functions in vitro and in vivo, and determine the signal transduction pathways activated in cultured vascular endothelial and smooth muscle cells by the three isoforms of adiponectin, focusing initially on the AMP- activated protein kinase, and NF-kB, MAP kinase, and NO pathways. Cells from T-cadherin -/- mice will allow us to continue to explore the role of this receptor in adiponectin signaling and localization in the vasculature. Importantly, with Projects I and II we will determine the effects of the various isoforms and orthologs of adiponectin and of T-cadherin on blood vessel endothelial and smooth muscle cells and on atherosclerosis and CHD in apoE -/- and SR-BI/apoE double knockout (dKO) mice. Thus, over the coming five years we hope to elucidate the roles of adiponectin and its principal vascular binding protein, T-cadherin, in maintaining the normal state of vascular endothelial and smooth muscle cells, and understand whether and how deletion of either of these proteins leads to atherosclerosis, thrombosis and CHD.

我们的总体目标是了解脂肪因子脂联素在血管功能、动脉粥样硬化、 和冠心病。脂联素仅由脂肪细胞产生，并且含量很高 存在于几种血管周围的内膜中。脂联素在调节中起关键作用 肝脏和肌肉的脂肪和葡萄糖代谢以及血管的代谢和增殖 平滑肌和可能的内皮细胞。我们鉴定了几种脂联素直向同源物，表达 主要由与脂联素具有相同生物活性和信号传导特性的脂肪细胞组成；这些，比如 脂联素，可调节血管细胞的代谢。脂联素信号传导的特性 受体和信号转导途径未知；我们和其他实验室已经明确表明 据先前报道，脂联素的假定信号受体不能以这种能力发挥作用。我们 鉴定出 T-钙粘蛋白（一种 GPI 锚定表面蛋白）作为脂联素结合蛋白，具有高度和 由血管内膜细胞特异性表达。小鼠体内 T-钙粘蛋白的缺失会导致 脉管系统中脂联素的减少和循环的显着增加，表明它是一个主要的 脂联素受体。然而，需要额外的细胞表面受体来介导脂联素 发信号。我们将克隆这些信号脂联素受体，分析它们的结构和功能 体外和体内，并确定培养的血管内皮细胞中激活的信号转导途径 和平滑肌细胞由脂联素的三种亚型组成，首先关注 AMP 激活的 蛋白激酶、NF-kB、MAP 激酶和 NO 途径。来自 T-钙粘蛋白 -/- 小鼠的细胞将使我们能够 继续探索该受体在脂联素信号传导和脉管系统定位中的作用。 重要的是，通过项目 I 和 II，我们将确定各种异构体和直系同源物的影响 脂联素和 T-钙粘蛋白对血管内皮细胞和平滑肌细胞的影响 apoE -/- 和 SR-BI/apoE 双敲除 (dKO) 小鼠中的动脉粥样硬化和冠心病。因此，超过 未来五年，我们希望阐明脂联素及其主要血管结合蛋白的作用， T-钙粘蛋白，维持血管内皮细胞和平滑肌细胞的正常状态，以及 了解这些蛋白质的缺失是否以及如何导致动脉粥样硬化、血栓形成和 冠心病。