Class B Scavenger Receptors and Atherosclerosis

B 类清道夫受体与动脉粥样硬化

• 批准号: 7798400
• 负责人: Deneys Rem Van Der Westhuyzen
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7798400
• 关键词: Affect; Antiatherogenic; Arterial Fatty Streak; Arteries; Atherosclerosis; Bone Marrow Transplantation; CD36 gene; Cardiovascular Diseases; Cause of Death; Cell membrane; Cells; Cholates; Cholesterol; Chronic; Complex; Development; Diet; Disease; Exhibits; Extrahepatic; Fatty acid glycerol esters; Financial compensation; Foam Cells; Genes; Hepatic; Homeostasis; Host Defense; Immune system; Inflammation; Inflammatory; Inflammatory Response Pathway; Knock-out; Knockout Mice; LDL Cholesterol Lipoproteins; Lesion; Lipids; Lipopolysaccharides; Lipoprotein Receptor; Lipoproteins; Liver; Low-Density Lipoproteins; Measures; Metabolic; Metabolism; Microarray Analysis; Mus; Nature; Pathway interactions; Pattern recognition receptor; Plasma; Play; Regulation; Risk Factors; Role; SR-B proteins; SR-BI receptor; Signal Pathway; Signal Transduction; TLR4 gene; Testing; Tissues; Transplantation; United States; Veterans; atherogenesis; base; drug development; feeding; macrophage; mouse model; oxidized low density lipoprotein; protein expression; public health relevance; receptor; research study; response; reverse cholesterol transport; scavenger receptor; treatment strategy; uptake

DESCRIPTION (provided by applicant): The roles of the Class B scavenger receptors, SR-BI and CD36, in the development of atherosclerotic disease, a major cause of death, remain poorly understood. This is due in part to the varied and still little understood functions of these two pattern recognition receptors in host defense and tissue homeostasis. The role of CD36 in the initiation of macrophage foam cell formation is controversial, although CD36 has the ability to take up modified lipoproteins such as oxidized LDL. Other potentially important functions of CD36 include its role in the innate immune system and its role in inflammatory signaling. Atherosclerosis is a chronic inflammatory disease and we propose that CD36 plays a more complex role in atherosclerotic lesion formation. The structurally closely related receptor, SR-BI, plays a key role in reverse cholesterol transport to the liver and has been shown in several mouse models to be anti-atherogenic. Recent findings have also indicated additional extrahepatic roles of SR-BI in atherogenesis, including effects in macrophages. The functional basis for these effects is not known, although we have shown that SR-BI-null mice have a markedly enhanced inflammatory cytokine response and higher lethality in response to lipopolysaccharide (LPS). Furthermore, mice deficient in both SR-BI and CD36 unexpectedly exhibit much greater atherosclerotic lesion formation than mice lacking either SR-BI or CD36 only. These findings indicate that SR-BI and CD36 each have athero-protective functions, yet to be defined. The protective functions of the two receptors may be overlapping allowing at least partial compensation in mice lacking only one of the two receptors. The central hypothesis of this proposal is that SR-BI and CD36 act in a complementary or synergistic manner to protect against atherosclerosis. We propose that SR-BI and CD36 are key to the innate defense against atherosclerosis, a chronic inflammatory disease. The following 4 objectives are proposed to examine these hypotheses: Objective 1 will examine the complementary roles SR-BI and CD36 in atherosclerotic lesion formation in response to high fat diets. This will be accomplished by analyzing the extent and nature of aortic lesions in wild type, SR-BI-null, CD36-null and SR-BI-nullXCD36-null mice. Objective 2 will investigate the roles of macrophage-expressed Class B scavenger receptors in atherosclerosis. This will be accomplished through the use of bone marrow transplantation. Objective 3 will identify the complementary or synergistic roles of SR-B1 and CD36 in macrophage foam cell formation. This will be accomplished by measuring lipid accumulation in wild type and SR-BI-XCD36- DKO macrophages treated with modified LDLs. Cells will be examined for lipid related protein expression and by gene microarray analysis. Lipid uptake and efflux pathways will be compared. Objective 4 will investigate enhanced inflammatory signaling in CD36/SR-BI DKO macrophages and its effects on macrophage lipid accumulation. The impact of inflammatory signaling on modified LDL uptake in primary macrophages will be evaluated together with the hypothesis that increased plasma membrane cholesterol content in SR-BIxCD36 DKO macrophages stimulates inflammatory signaling pathways. These studies are expected to provide new understanding of the metabolic functions of CD36 and SR-BI as well as their role in atherosclerosis. PUBLIC HEALTH RELEVANCE: Cardiovascular disease remains the number one killer in the United States and among veterans. Although widely studied, the mechanisms underlying atherosclerosis are not yet clearly understood. Plasma cholesterol and LDL levels are a major risk factor for atherosclerosis but the underlying mechanisms for this are still poorly understood. Further understanding of how LDL cholesterol accumulates in the artery wall and the roles of the various receptors for lipoproteins will potentially allow for the identification of new treatment strategies and new drug development.

描述（由申请人提供）： B 类清道夫受体 SR-BI 和 CD36 在动脉粥样硬化疾病（死亡的主要原因）的发展中的作用仍然知之甚少。这部分是由于这两种模式识别受体在宿主防御和组织稳态中的功能多种多样且仍知之甚少。尽管 CD36 具有吸收修饰脂蛋白（如氧化 LDL）的能力，但 CD36 在巨噬细胞泡沫细胞形成起始中的作用仍存在争议。 CD36 的其他潜在重要功能包括其在先天免疫系统中的作用及其在炎症信号传导中的作用。动脉粥样硬化是一种慢性炎症性疾病，我们认为CD36在动脉粥样硬化病变形成中发挥着更复杂的作用。结构上密切相关的受体 SR-BI 在逆转胆固醇转运至肝脏方面发挥着关键作用，并已在多种小鼠模型中显示出抗动脉粥样硬化作用。最近的研究结果还表明 SR-BI 在动脉粥样硬化形成中的其他肝外作用，包括对巨噬细胞的影响。这些作用的功能基础尚不清楚，尽管我们已经证明 SR-BI 缺失小鼠的炎症细胞因子反应显着增强，并且对脂多糖 (LPS) 的反应具有更高的致死率。此外，与仅缺乏SR-BI或CD36的小鼠相比，同时缺乏SR-BI和CD36的小鼠意外地表现出更大的动脉粥样硬化病变形成。这些发现表明 SR-BI 和 CD36 均具有动脉粥样硬化保护功能，但尚未明确。这两种受体的保护功能可能是重叠的，从而允许在仅缺乏这两种受体之一的小鼠中至少部分补偿。该提案的中心假设是 SR-BI 和 CD36 以互补或协同的方式发挥作用，防止动脉粥样硬化。我们认为 SR-BI 和 CD36 是对抗动脉粥样硬化（一种慢性炎症性疾病）的先天防御的关键。提出以下 4 个目标来检验这些假设： 目标 1 将检验 SR-BI 和 CD36 在响应高脂肪饮食的动脉粥样硬化病变形成中的互补作用。这将通过分析野生型、SR-BI-null、CD36-null 和 SR-BI-nullXCD36-null 小鼠的主动脉病变的程度和性质来完成。目标 2 将研究巨噬细胞表达的 B 类清道夫受体在动脉粥样硬化中的作用。这将通过使用骨髓移植来实现。目标 3 将确定 SR-B1 和 CD36 在巨噬细胞泡沫细胞形成中的互补或协同作用。这将通过测量野生型和用修饰的 LDL 处理的 SR-BI-XCD36-DKO 巨噬细胞中的脂质积累来实现。将检查细胞的脂质相关蛋白表达和基因微阵列分析。将比较脂质摄取和流出途径。目标 4 将研究 CD36/SR-BI DKO 巨噬细胞中炎症信号的增强及其对巨噬细胞脂质积累的影响。炎症信号传导对原代巨噬细胞中修饰的 LDL 摄取的影响将与 SR-BIxCD36 DKO 巨噬细胞中质膜胆固醇含量增加刺激炎症信号传导途径的假设一起进行评估。这些研究有望为 CD36 和 SR-BI 的代谢功能及其在动脉粥样硬化中的作用提供新的认识。 公共卫生相关性： 心血管疾病仍然是美国和退伍军人的头号杀手。尽管进行了广泛的研究，但动脉粥样硬化的机制尚不清楚。血浆胆固醇和低密度脂蛋白水平是动脉粥样硬化的主要危险因素，但其潜在机制仍知之甚少。进一步了解低密度脂蛋白胆固醇如何在动脉壁中积聚以及各种脂蛋白受体的作用将有可能有助于确定新的治疗策略和新药物的开发。