Adiponectin in Cardiovascular Biology and Pathology

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，含量较高。 在几种血管周围的内膜中。脂联素在调控中起着关键作用 肝脏和肌肉的脂肪和葡萄糖代谢以及血管的代谢和增殖 可能还有血管内皮细胞。我们鉴定了几个脂联素同源基因，表达了 主要是通过脂肪细胞，这些脂肪细胞与脂联素具有共同的生物学活性和信号特性； 脂联素可能调节血管细胞的代谢。脂联素信号转导的同源性 受体和信号转导途径尚不清楚；我们和其他实验室已经明确表示 此前报道，脂联素的信号受体并不具有这种功能。我们 T-钙粘蛋白，一种GPI锚定的表面蛋白，是一种脂联素结合蛋白，高度和 由血管内膜中的细胞特异性表达。T-钙粘附素在小鼠体内的缺失导致 血管中脂联素的减少和循环中的主要增加，表明它是一种主要的 脂联素受体。然而，额外的细胞表面受体是调节脂联素所必需的。 发信号。我们将克隆这些信号转导的脂联素受体，分析它们的结构和功能 体外和体内，并确定在培养的血管内皮细胞激活的信号转导通路 而平滑肌细胞则由三种不同亚型的脂联素组成，最初集中在AMP激活的 蛋白激酶、核因子-kB、MAP激酶，以及NO途径。来自T-钙粘蛋白-/-小鼠的细胞将允许我们 继续探索该受体在脂联素信号转导中的作用以及在血管系统中的定位。 重要的是，在项目I和项目II中，我们将确定各种异构体和同源异构体的影响 脂联素和T-钙粘附素在血管内皮细胞和平滑肌细胞上的表达及意义 ApoE-/-和SR-BI/apoE双基因敲除(DKO)小鼠的动脉粥样硬化和冠心病因此，在过去的时间里 在接下来的五年里，我们希望阐明脂联素及其主要血管结合蛋白的作用， T-钙粘附素，维持血管内皮细胞和平滑肌细胞的正常状态，以及 了解这两种蛋白缺失是否以及如何导致动脉粥样硬化、血栓形成和 先心病。

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.