ROLE OF CD36 IN NUTRIENT DELIVERY AND ITS DYSFUNCTION IN AFRICAN AMERICANS

CD36 在非裔美国人营养输送中的作用及其功能障碍

• 批准号: 9515993
• 负责人: Nada A. Abumrad
• 金额: $ 49.66万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9515993
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adipose tissue; Adult; Affinity; African American; Age-Years; Alleles; Arginine; Binding; Biological Markers; Blood Vessels; CD36 gene; CD47 gene; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cell physiology; Cells; Chronic; Chylomicrons; Clinical; Closure by clamp; Code; Complex; Coronary heart disease; Cyclic GMP; Data; Dementia; Diabetes Mellitus; Diet; Disease susceptibility; Endothelial Cells; Etiology; Event; Fat emulsion; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Generations; Genetic Markers; Genetic Polymorphism; Glucose; Guide prevention; Heparin; Human; Hypertension; Immunity; Impairment; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Interdisciplinary Study; Kidney Failure; Lead; Ligands; Ligation; Lipids; Magnetic Resonance; Mediating; Membrane Proteins; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Microcirculation; Molecular; Mus; Muscle; Mutate; Myocardial Infarction; Nitric Oxide; Nutrient; Obesity; Outcome; Palmitic Acids; Pathway interactions; Perfusion; Phosphorylation; Physiological; Predisposition; Prevention approach; Production; Proteins; Regulation; Risk; Role; SR-BI receptor; Scientist; Signal Transduction; Sildenafil citrate; Specificity; Spin Labels; Stroke; Taste Perception; Testing; Thrombospondin 1; Tissues; Vasodilation; Vasodilator Agents; Work; base; endothelial dysfunction; fatty acid oxidation; feeding; genetic variant; glucose uptake; improved; in vivo; inhibitor/antagonist; insight; insulin sensitivity; insulin signaling; long chain fatty acid; loss of function; mortality; mouse model; novel; phosphodiesterase V; receptor; recruit; response; scavenger receptor; sildenafil; uptake

ABSTRACT: The scavenger receptor CD36 has lipid and non-lipid ligands and versatile functions in metabolism and immunity. An important function of CD36 is its ability to transduce intracellular signals triggered by its ligands. CD36 signaling contributes to the regulation of several aspects of fatty acid (FA) utilization such as fat taste perception, chylomicron production, enteroendocrine secretion, FA oxidation etc. We recently showed that CD36 interacts with the AMPK and insulin signaling pathways and we propose that this mediates an important part of its actions on nutrient utilization. We document presence of CD36 in a molecular complex with insulin receptor beta (IRβ) and CD36-mediated recruitment to IRβ of Fyn and the catalytic p85 subunit of PI3-kinase. We also find that palmitic acid binding to CD36 interferes with Fyn and p85 recruitment and blunts Akt phosphorylation. In this project, which involves a multidisciplinary collaboration between basic and clinical scientists, we will test the novel hypothesis that the membrane protein CD36 via its interaction with the PI3K pathway influences endothelial cell function, insulin’s action on microvasculature recruitment and consequently nutrient flux and the effect of high fat feeding to cause endothelial dysfunction. Our preliminary data document diminished vascular compliance in CD36-/- mice and more importantly in African Americans carrying coding SNP rs3211938 that reduces CD36 level by 50%. We will examine the functional implications of CD36 signaling in endothelial cells and the consequences of endothelial cell CD36 deletion in mice on vascular function and insulin regulation of tissue perfusion and energetics. We will determine in these mice the effect of high fat feeding to induce endothelial dysfunction and whether this is reversed by treatment with phosphodiesterase 5 (PDE5) inhibition which blocks cGMP degradation. In a parallel approach we will examine influence of partial CD36 deficiency in African American carriers of rs3211938 on endothelial dysfunction, microvascular recruitment by insulin and the efficacy of PDE5 inhibition treatment. Obesity and endothelial dysfunction are highly prevalent especially in African Americans and associate with negative cardiovascular and metabolic outcomes. The proposed work will provide fundamental information that is currently unavailable and that could influence treatment of endothelial dysfunction and insulin resistance in humans.

摘要： 清道夫受体CD36具有脂类和非脂类配体，具有多种代谢和功能。 豁免权。CD36的一个重要功能是能够传递由其配体触发的细胞内信号。 CD36信号参与调节脂肪酸(FA)利用的几个方面，如脂肪味道 感知、乳胶粒产生、肠道内分泌、FA氧化等。我们最近发现 CD36与AMPK和胰岛素信号通路相互作用，我们认为这介导了一个重要的 它在养分利用方面的部分作用。我们发现CD36存在于与胰岛素的分子复合体中。 受体β(IRβ)和CD36介导Fyn的IRβ和PI3K催化的P85亚单位的募集。 我们还发现，棕榈酸与CD36的结合干扰了Fyn和P85的招募，并钝化了Akt 磷酸化。在这个项目中，涉及基础和临床之间的多学科合作 科学家们，我们将测试这一新的假设，即膜蛋白CD36通过与PI3K的相互作用 途径影响内皮细胞功能，胰岛素对微血管系统募集的作用，从而 营养流通量和高脂饮食对内皮功能障碍的影响。我们的初步数据文档 CD36-/-小鼠的血管顺应性降低，更重要的是，在携带编码的非裔美国人中 SNP rs3211938使CD36水平降低50%。我们将研究CD36的功能含义 血管内皮细胞信号转导及内皮细胞CD36缺失对血管的影响 组织灌流和能量学的功能和胰岛素调节。我们将在这些小鼠身上确定 高脂饮食诱导血管内皮细胞功能障碍及应用 磷酸二酯酶5(PDE5)抑制cGMP降解。在一种平行的方法中，我们将检查 非裔美国人rs3211938携带者部分CD36缺陷对内皮功能障碍的影响 胰岛素对微血管募集及PDE5抑制治疗的影响。肥胖与血管内皮细胞 功能障碍非常普遍，特别是在非裔美国人中，并与阴性心血管疾病有关 和新陈代谢结果。拟议的工作将提供目前无法获得的基本信息 这可能会影响人类内皮功能障碍和胰岛素抵抗的治疗。