Endothelial SR-BI and Metabolic Health

内皮 SR-BI 和代谢健康

• 批准号: 9302510
• 负责人: Chieko Mineo
• 金额: $ 40.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-14 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302510
• 关键词: Adaptor Signaling Protein; Adipose tissue; Adult; Affinity; Animal Model; Apolipoprotein A-I; Apolipoproteins; Attenuated; BCR gene; Centers for Disease Control and Prevention (U.S.); Diabetes Mellitus; Disease; Endothelial Cells; Endothelium; Enterobacteria phage P1 Cre recombinase; Fasting; Genetically Engineered Mouse; Glucose; Glucose Intolerance; Goals; Health; High Density Lipoproteins; Homeostasis; Human; Hyperglycemia; Hyperinsulinism; Impairment; Inflammation; Inflammatory Response; Insulin; Insulin Resistance; Intervention; Intervention Studies; Knockout Mice; Laboratories; Life Style; Link; Lipids; Lipoprotein (a); Lipoprotein Binding; LoxP-flanked allele; Mediating; Metabolic; Metabolic syndrome; Molecular; Mouse Strains; Mus; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Pharmacology; Phosphorylation; Phosphotransferases; Plasma; Play; Prevalence; Prevention; Process; Production; Protein-Serine-Threonine Kinases; Regulation; Research; Risk Factors; Role; SR-BI receptor; Signal Pathway; Signal Transduction; Skeletal Muscle; Testing; Wild Type Mouse; Work; base; blood glucose regulation; cadherin 5; disorder prevention; endothelial dysfunction; experimental study; falls; gain of function; glucose disposal; high density lipoprotein receptor; improved; insulin sensitivity; macrophage; metabolic phenotype; mouse model; new therapeutic target; novel; novel therapeutic intervention; overexpression; prevent; programs; promoter; public health relevance; receptor; reconstitution; scavenger receptor; success; trend

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.

描述（由申请人提供）：2 型糖尿病（T2DM）和代谢综合征的患病率在过去几十年中迅速增加。通过药物干预和生活方式改变来预防和治疗这些疾病的成功有限，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，对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，人们对 HDL 发挥这些作用的机制知之甚少。我们之前的工作表明，HDL 与其受体 B 型清道夫受体 I 型 (SR-BI) 结合可有效激活内皮 NO 合酶 (eNOS) 并增强 NO 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，在葡萄糖和胰岛素稳态异常中起着因果作用。为了确定内皮细胞中的 HDL-SR-BI 是否在葡萄糖稳态中发挥作用，我们最近评估了内皮细胞中 SR-BI 特异性缺失的小鼠的代谢表型。我们发现，与对照同窝小鼠相比，这些小鼠出现葡萄糖不耐受和胰岛素抵抗。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 SR-BI 调节葡萄糖稳态的机制。目标 1 将确定由内皮 SR-BI 介导的葡萄糖稳态控制机制。使用内皮 SR-BI 缺失的小鼠，目标 1 将检验以下假设：内皮 SR-BI 通过促进骨骼肌葡萄糖输送和预防脂肪组织中的炎症反应，在正常葡萄糖稳态中发挥重要作用。目标 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 的作用将通过使用小鼠模型的功能丧失和获得策略来确定。我们将检验 HDL 通过需要内皮 SR-BI、PDZK1、eNOS 激活并由此产生 NO 的过程来促进胰岛素敏感性的假设。目标 3 将确定 SR-BI 如何独特地启动内皮信号传导。基于我们最近发现 PDZK1 与内皮细胞中的丝氨酸/苏氨酸激酶 Bcr（断点簇区域）相互作用，我们将测试以下假设：HDL 刺激 Bcr 激酶导致 Bcr 底物磷酸化，将 SR-BI 和 PDZK1 与 eNOS 激活联系起来，并且 Bcr 是正常葡萄糖稳态和胰岛素敏感性所必需的 高密度脂蛋白。通过实现拟议的具体目标，我们的研究计划将揭示新的机制，从而确定新的治疗靶点，以预防和治疗与低 HDL 水平相关的胰岛素抵抗和 T2DM，这两者都是代谢综合征的关键特征。