Endothelial SR-BI and Metabolic Health

描述（由申请人提供）：在过去的几十年里，2型糖尿病（T2DM）和代谢综合征的患病率迅速增加。通过药物干预和改变生活方式预防和治疗这些疾病的成功率有限，迫切需要新的治疗方法。血浆高密度脂蛋白（HDL）水平低是代谢综合征的标志，也是T2DM的既定危险因素，人类和动物模型的研究表明HDL对葡萄糖稳态有积极影响；然而，HDL发挥这些作用的机制尚不清楚。我们之前的研究表明，HDL与其受体清道夫受体B类I型（SR-BI）结合可有效激活内皮NO合成酶（eNOS）并促进NO的产生。越来越多的证据表明，内皮功能障碍，特别是一氧化氮生成减少，在异常的葡萄糖和胰岛素稳态中起着因果作用。为了确定内皮细胞中的HDL-SR-BI是否在葡萄糖稳态中起作用，我们最近评估了内皮细胞中SR-BI特异性缺失小鼠的代谢表型。我们发现，与对照组相比，这些小鼠出现了葡萄糖耐受不良和胰岛素抵抗。从这些令人惊讶的发现出发，该项目的总体目标是确定内皮细胞SR-BI调节葡萄糖稳态的机制。目的1将确定由内皮细胞SR-BI介导的葡萄糖稳态调节机制。使用内皮细胞SR-BI缺失的小鼠，Aim 1将验证内皮细胞SR-BI通过促进骨骼肌葡萄糖输送和防止脂肪组织炎症反应在正常葡萄糖稳态中起主要作用的假设。目的2将确定由SR-BI介导的调节葡萄糖稳态的分子途径。HDL、PDZK1和NO的作用将通过小鼠模型的功能丧失和功能获得策略来确定。我们将验证HDL通过内皮细胞SR-BI、PDZK1、eNOS激活和NO生成的过程促进胰岛素敏感性的假设。目的3将确定SR-BI如何独特地启动内皮细胞中的信号传导。基于我们最近的发现，PDZK1与内皮中丝氨酸/苏氨酸激酶Bcr（断点集群区）相互作用，我们将验证HDL刺激Bcr激酶导致Bcr底物磷酸化的假设，该底物将SR-BI和PDZK1与eNOS激活联系起来，并且Bcr是HDL提供的正常葡萄糖稳态和胰岛素敏感性所必需的。通过完成提出的具体目标，我们的研究计划将揭示新的机制，从而确定新的治疗靶点，以预防和治疗胰岛素抵抗和与低水平HDL相关的T2DM，这两者都是代谢综合征的关键特征。

DESCRIPTION (provided by applicant): The prevalence of type 2 diabetes mellitus (T2DM) and the metabolic syndrome has rapidly increased over the past several decades. Prevention and treatment of these diseases through pharmacological interventions and lifestyle changes have limited success, and novel therapeutic approaches are urgently needed. Low levels of plasma high-density lipoprotein (HDL) are a hallmark of the metabolic syndrome and an established risk factor for T2DM, and studies in humans and in animal models indicate that HDL positively influences glucose homeostasis; however, the mechanism by which HDL exerts these effects is poorly understood. Our previous work demonstrated that HDL binding to its receptor Scavenger Receptor Class B Type I (SR-BI) potently activates endothelial NO synthase (eNOS) and enhances NO production. Growing body of evidence indicates that endothelial dysfunction, particularly decreased NO production, plays a causal role in abnormal glucose and insulin homeostasis. To determine whether HDL-SR-BI in endothelial cells plays a role in glucose homeostasis, we have recently assessed metabolic phenotypes in mice with specific deletion of SR-BI in endothelial cells. We found that these mice develop glucose intolerance and insulin resistance compared with control littermates. Springboarding from these surprising discoveries, the overall goal of the proposed project is to determine the mechanism by which endothelial SR-BI regulates glucose homeostasis. Aim 1 will determine the mechanisms governing glucose homeostasis that are mediated by endothelial SR-BI. Using the mice with endothelial SR-BI deletion, Aim 1 will test the hypothesis that endothelial SR-BI plays a major role in normal glucose homeostasis by promoting skeletal muscle glucose delivery and by preventing inflammatory responses in adipose tissues. Aim 2 will identify the molecular pathway that regulates glucose homeostasis mediated by SR-BI. Roles of HDL, PDZK1 and NO will be determined by loss- and gain-of-function strategies using mouse models. We will test the hypothesis that HDL promotes insulin sensitivity through the process that requires endothelial SR-BI, PDZK1, eNOS activation and resulting production of NO. Aim 3 will determine how SR-BI uniquely initiates signaling in endothelium. Based upon our recent discovery that PDZK1 interacts with the serine/threonine kinase Bcr (Breakpoint cluster region) in endothelium, we will test the hypothesis that HDL stimulates Bcr kinase to result in phosphorylation of a Bcr substrate that links SR-BI and PDZK1 to eNOS activation and that Bcr is required for normal glucose homeostasis and insulin sensitivity afforded by HDL. By accomplishing the proposed Specific Aims, our research program will reveal novel mechanisms and thereby identify new therapeutic targets to prevent and treat insulin resistance and T2DM associated with low levels of HDL, both of which are key features of the metabolic syndrome.