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.

抽象的： 清道夫受体 CD36 具有脂质和非脂质配体，在代谢和代谢中具有多种功能。 免疫。 CD36 的一个重要功能是其转导由其配体触发的细胞内信号的能力。 CD36 信号传导有助于调节脂肪酸 (FA) 利用的多个方面，例如脂肪味道 感知、乳糜微粒的产生、肠内分泌、FA 氧化等。我们最近表明 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作用 其养分利用行动的一部分。我们记录了 CD36 与胰岛素的分子复合物的存在 受体β (IRβ) 和 CD36 介导的 Fyn IRβ 和 PI3 激酶催化 p85 亚基的募集。 我们还发现棕榈酸与 CD36 结合会干扰 Fyn 和 p85 募集并削弱 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，我们将测试膜蛋白 CD36 通过与 PI3K 相互作用的新假设 该途径影响内皮细胞功能、胰岛素对微血管募集的作用，从而影响 营养通量和高脂肪喂养导致内皮功能障碍的影响。我们的初步数据文件 CD36-/- 小鼠的血管顺应性降低，更重要的是携带编码的非洲裔美国人的血管顺应性降低 SNP rs3211938 可将 CD36 水平降低 50%。我们将研究 CD36 的功能含义 小鼠内皮细胞信号转导以及内皮细胞 CD36 缺失对血管的影响 组织灌注和能量的功能和胰岛素调节。我们将确定这些小鼠的效果 高脂肪喂养会诱发内皮功能障碍，以及这种情况是否可以通过治疗来逆转 磷酸二酯酶 5 (PDE5) 抑制可阻止 cGMP 降解。在并行方法中，我们将检查 非洲裔美国 rs3211938 携带者部分 CD36 缺陷对内皮功能障碍的影响， 胰岛素的微血管募集和 PDE5 抑制治疗的功效。肥胖与内皮细胞 功能障碍非常普遍，尤其是在非裔美国人中，并与心血管疾病相关 和代谢结果。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。