Endothelial SR-BI and Metabolic Health

内皮 SR-BI 和代谢健康

• 批准号: 9127359
• 负责人: Chieko Mineo
• 金额: $ 40.48万
• 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/9127359
• 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; Fasting; Genetically Engineered Mouse; Glucose; Glucose Intolerance; Goals; Health; High Density Lipoproteins; Homeostasis; Human; Hyperglycemia; Hyperinsulinism; 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; 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; falls; gain of function; glucose disposal; high density lipoprotein receptor; improved; insulin sensitivity; lifestyle intervention; macrophage; metabolic phenotype; mouse model; new therapeutic target; novel; novel therapeutic intervention; overexpression; prevent; programs; promoter; receptor; recombinase; reconstitution; research study; 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）：在过去的几十年中，2型糖尿病（T2DM）和代谢综合征的患病率迅速增加。通过药理学干预和生活方式改变对这些疾病的预防和治疗的成功有限，并且迫切需要新颖的治疗方法。低水平的血浆高密度脂蛋白（HDL）是代谢综合征的标志和T2DM的既定危险因素，对人类和动物模型的研究表明，HDL对葡萄糖稳态产生积极影响；但是，HDL发挥这些作用的机制知之甚少。我们以前的工作表明，HDL与其受体清道夫受体I类（SR-BI）的结合有效地激活内皮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，特别是没有产生的降低，在异常葡萄糖和胰岛素稳态中起因果作用。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特异性缺失的小鼠中的代谢表型。我们发现，与对照窝窝相比，这些小鼠会产生葡萄糖不耐症和胰岛素抵抗。这些令人惊讶的发现，拟议项目的总体目标是确定内皮SR-BI调节葡萄糖稳态的机制。 AIM 1将确定由内皮SR-BI介导的葡萄糖稳态的机制。 AIM 1使用带有内皮SR-BI缺失的小鼠，将检验以下假设：内皮SR-BI通过促进骨骼肌葡萄糖递送并防止脂肪组织中的炎症反应，在正常的葡萄糖稳态中起主要作用。 AIM 2将确定调节由SR-BI介导的葡萄糖稳态的分子途径。 HDL，PDZK1和NO的角色将由使用鼠标模型的功能损失和功能获得策略来确定。我们将测试HDL通过需要内皮SR-BI，PDZK1，ENOS激活并产生NO的过程来促进胰岛素灵敏度的假设。 AIM 3将确定SR-BI如何唯一启动内皮中的信号传导。基于我们最近的发现，即PDZK1与内皮中的丝氨酸/苏氨酸激酶BCR（断点群集区域）相互作用，我们将测试HDL刺激HDL刺激BCR激酶的假说，以使SR和PDZK1的正常脉络性与enos ructies相关，以使BCR的磷酸化导致SR-BI和PDZK1的正常脉络性，使其正常地固定在HINDIS上。 HDL。通过实现提出的特定目标，我们的研究计划将揭示新的机制，从而确定新的治疗靶标，以预防和治疗与低水平HDL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。