Class B Scavenger Receptors and Atherosclerosis

B 类清道夫受体与动脉粥样硬化

• 批准号: 8195617
• 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/8195617
• 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

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.

B类清道夫受体SR-BI和CD 36在肿瘤发生发展中的作用 动脉粥样硬化疾病是一种主要死亡原因，人们对它的了解仍然很少。这部分是由于 这两种模式识别受体在宿主防御中的功能各不相同，但仍知之甚少 和组织内环境稳定。CD 36在巨噬细胞泡沫细胞形成起始中的作用是 尽管CD 36具有吸收修饰的脂蛋白如氧化的LDL的能力，但这是有争议的。 CD 36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免疫系统中的作用。 在炎症信号中的作用。动脉粥样硬化是一种慢性炎症性疾病，我们建议 CD 36在动脉粥样硬化病变形成中起着更为复杂的作用。结构紧密 相关受体SR-BI在胆固醇向肝脏的逆向转运中起关键作用， 在几种小鼠模型中显示出抗动脉粥样硬化。最近的调查结果还表明， SR-BI在动脉粥样硬化形成中的其他肝外作用，包括在巨噬细胞中的作用。的 这些作用的功能基础尚不清楚，尽管我们已经表明SR-BI-null小鼠具有 显著增强的炎性细胞因子反应和更高的致死率， 脂多糖（LPS）。此外，SR-BI和CD 36两者缺陷的小鼠出乎意料地表现出 比仅缺乏SR-BI或CD 36的小鼠更大的动脉粥样硬化病变形成。这些 研究结果表明，SR-BI和CD 36各自具有动脉粥样硬化保护功能，但尚未确定。的 两种受体的保护功能可以重叠 只缺少其中一种受体的小鼠。该提议的中心假设是SR-BI 和CD 36以互补或协同的方式起作用以防止动脉粥样硬化。我们 提出SR-BI和CD 36是对抗动脉粥样硬化的先天防御的关键， 炎症性疾病。提出了以下4个目标来检验这些假设： 目的1探讨SR-BI和CD 36在动脉粥样硬化病变中的互补作用 高脂肪饮食反应的形成。这将通过分析其程度和性质来实现 在野生型、SR-BI-null、CD 36-null和SR-BI-null × CD 36-null小鼠中的主动脉病变。目标2将 探讨巨噬细胞表达的B类清道夫受体在动脉粥样硬化中的作用。这 将通过骨髓移植来实现。目标3将确定 SR-B1和CD 36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SR-BI-XCD 36- DKO中的脂质积累来实现 用修饰的LDL处理的巨噬细胞。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CD 36/SR-BI DKO巨噬细胞中增强的炎症信号传导及其对 巨噬细胞脂质积聚。炎症信号传导对大鼠LDL摄取的影响 将评价原代巨噬细胞，同时假设血浆中 SR-BIxCD 36 DKO巨噬细胞中的膜胆固醇含量刺激炎症信号传导 途径。这些研究有望为人类提供新的认识， CD 36和SR-BI及其在动脉粥样硬化中的作用