Class B Scavenger Receptors and Atherosclerosis

描述(由申请人提供)： B类清道夫受体SR-BI和CD36在动脉粥样硬化性疾病的发展中的作用仍然知之甚少，而动脉粥样硬化性疾病是导致死亡的主要原因。这在一定程度上是由于这两种模式识别受体在宿主防御和组织动态平衡中的不同功能，但仍鲜为人知。CD36在启动巨噬细胞泡沫细胞形成中的作用存在争议，尽管CD36具有摄取氧化低密度脂蛋白等修饰脂蛋白的能力。CD36的其他潜在重要功能包括它在先天免疫系统中的作用以及它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，我们认为CD36在动脉粥样硬化病变的形成中起着更为复杂的作用。结构上密切相关的受体SR-BI在胆固醇反向转运到肝脏中发挥关键作用，并已在几个小鼠模型中被证明具有抗动脉粥样硬化作用。最近的发现也表明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。这些效应的功能基础尚不清楚，尽管我们已经证明SR-BI缺失小鼠的炎性细胞因子反应显著增强，并且对内毒素(LPS)的致死率更高。此外，同时缺乏SR-BI和CD36的小鼠意外地比只缺乏SR-BI或CD36的小鼠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各自具有动脉粥样硬化保护功能，但尚未确定。这两种受体的保护功能可能是重叠的，至少可以在缺乏两种受体中的一种的小鼠身上进行部分补偿。这一建议的中心假设是SR-BI和CD36以互补或协同的方式发挥作用，以防止动脉粥样硬化。我们认为SR-BI和CD36是抵抗动脉粥样硬化的关键，动脉粥样硬化是一种慢性炎症性疾病。以下4个目标被提出来检验这些假说：目标1将检验SR-BI和CD36在高脂饮食反应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-空、CD36-空和SR-BI-空XCD36-空小鼠的主动脉损伤的范围和性质来实现。目的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。这将通过使用骨髓移植来实现。目的3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低密度脂蛋白处理的野生型和SR-BI-XCD36-DKO巨噬细胞中的脂质积累来实现。将通过基因微阵列分析来检查细胞中脂质相关蛋白的表达。我们将比较脂肪摄取和外流途径。目的探讨CD36/SR-BI DKO巨噬细胞炎症信号增强及其对巨噬细胞脂质聚集的影响。炎症信号对原代巨噬细胞摄取修饰低密度脂蛋白的影响将与SR-BIxCD36 DKO巨噬细胞质膜胆固醇含量增加刺激炎症信号通路的假设一起进行评估。这些研究有望对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理解。 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。尽管被广泛研究，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，但其潜在机制仍然知之甚少。进一步了解低密度脂蛋白胆固醇是如何在动脉壁中积聚的，以及各种脂蛋白受体的作用，可能有助于确定新的治疗策略和新药开发。

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.