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： 清道夫接收器CD36具有脂质和非脂质配体以及代谢中的多功能功能 免疫。 CD36的重要功能是它可以翻译由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）利用的几个方面，例如脂肪味 感知，乳糜微粒产生，肠内分泌分泌，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，我们建议这介导一个重要的 其对养分利用的行动的一部分。我们记录了与胰岛素分子复合物中CD36的存在 受体β（IRβ）和CD36介导的FYNIRβ和PI3-激酶的催化p85亚基的募集。 我们还发现，与CD36结合的棕榈酸会干扰FYN和P85募集，并钝化Akt 磷酸化。在这个项目中，涉及基本和临床之间的多学科合作 科学家，我们将检验新的假设，即膜蛋白CD36通过与PI3K的相互作用 途径会影响内皮细胞功能，胰岛素对微脉管系统的作用，因此 营养通量和高脂肪进食的影响会导致内皮功能障碍。我们的初步数据文档 CD36 - / - 小鼠的血管依从性降低，更重要的是携带编码的非裔美国人 SNP RS3211938将CD36水平降低了50％。我们将研究CD36的功能含义 内皮细胞中的信号传导以及血管上小鼠内皮细胞CD36缺失的后果 组织灌注和能量学的功能和胰岛素调节。我们将在这些小鼠中确定 高脂肪进食以诱导内皮功能障碍，以及是否通过治疗来逆转 磷酸二酯酶5（PDE5）抑制，阻塞CGMP降解。在一种平行的方法中，我们将检查 部分CD36缺乏对非裔美国人载体RS3211938对内皮功能障碍的影响， 通过胰岛素和PDE5抑制作用的效率进行微血管募集。肥胖和内皮 功能障碍非常普遍，尤其是在非洲裔美国人中，并且与心血管负相关 和代谢结果。拟议的工作将提供目前不可用的基本信息 这可能会影响人类内皮功能障碍和胰岛素抵抗的治疗。