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级清道夫受体SR-BI和CD36在动脉粥样硬化疾病的发展中的作用，这是死亡的主要原因，仍然了解不足。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样化且几乎没有理解的功能。 CD36在巨噬细胞泡沫细胞形成的启动中的作用是有争议的，尽管CD36具有吸收改良的脂蛋白（如氧化的LDL）的能力。 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，我们建议CD36在动脉粥样硬化病变形成中起更复杂的作用。与结构密切相关的受体SR-BI在反向胆固醇转运到肝脏中起关键作用，并且在几种小鼠模型中已显示出具有抗动脉粥样硬化的作用。最近的发现还表明，SR-BI在动脉粥样硬化中的其他肝外作用，包括巨噬细胞的作用。这些作用的功能基础尚不清楚，尽管我们已经表明SR-BI-NULL小鼠对脂多糖（LPS）的炎症细胞因子反应显着增强，致死性更高。此外，与仅缺少SR-BI或CD36的小鼠相比，缺乏SR-BI和CD36的小鼠出乎意料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各自具有动脉保护功能，尚未定义。两种受体的保护功能可能是重叠的，从而使仅缺少两个受体中的一个小鼠至少部分补偿。该提议的中心假设是SR-BI和CD36以互补或协同的方式起作用，以防止动脉粥样硬化。我们建议SR-BI和CD36是针对慢性炎症性疾病的动脉粥样硬化的先天防御的关键。提出了以下4个目标来检查这些假设：目标1将检查响应高脂肪饮食的动脉粥样硬化病变形成中SR-BI和CD36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实现。目标2将研究巨噬细胞表达的B类清除剂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。这将通过测量用改良LDL处理的野生型和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。将比较脂质摄取和外排途径。目标4将研究CD36/SR-BI DKO巨噬细胞中增强的炎症信号传导及其对巨噬细胞脂质积累的影响。炎症信号传导对原发性巨噬细胞中修饰的LDL摄取的影响将与以下假设一起评估，即SR-BIXCD36 DKO巨噬细胞中质膜胆固醇含量增加的假设刺激了炎症信号通路。预计这些研究将对CD36和SR-BI的代谢功能以及它们在动脉粥样硬化中的作用提供新的了解。 公共卫生相关性： 心血管疾病仍然是美国和退伍军人中排名第一的杀手。尽管经过广泛研究，但尚未清楚地了解动脉粥样硬化的机制。血浆胆固醇和LDL水平是动脉粥样硬化的主要危险因素，但是对此的潜在机制仍然很少了解。进一步了解LDL胆固醇如何在动脉壁中积聚以及各种受体在脂蛋白中的作用，将有可能识别新的治疗策略和新药物的开发。