MOLECULAR AND CELL BIOLOGY OF CD36 A TSP RECEPTOR

CD36是一种88kD的多功能跨膜糖蛋白 表达于血小板、单核细胞、巨噬细胞，某些特异体 上皮细胞和脂肪细胞。它已经被证明是一种 凝血酶原蛋白的细胞受体(TSP)和最近 被认为是氧化低分子的巨噬细胞清道夫受体 密度脂蛋白(OxLDL)。低密度脂蛋白的氧化与 动脉粥样硬化的发病机制是脂类积聚。 动脉粥样硬化斑块直接由氧化低密度脂蛋白内化引起 内膜巨噬细胞。此外，OxLDL与血管的相互作用 细胞可能导致细胞活化为血栓前状态， 致动脉粥样硬化的表型。这项提议的中心假设是 CD36是一个主要的巨噬细胞受体，结合和 内化配体，包括总悬浮蛋白和氧化低密度脂蛋白。重点将放在 明确CD36功能的分子基础并探讨其在细胞周期中的作用 动脉硬化。特定目标研究L将定义结构-功能 控制CD36受体-配体结合的关系。互动 将对TSP和氧化低密度脂蛋白进行研究。这些实验将 利用重组CD36多肽与固相和细胞结合 学习。具体目标2将定义人类通过哪些机制 巨噬细胞CD36内化配体。巨噬细胞的调节 CD36信使核糖核酸合成和表面蛋白表达 动脉粥样硬化形成和分化的介体将使用 核糖核酸酶保护试验和免疫显微镜检查。CD36介导的 内化途径和结构-功能关系 还将探讨治理内部化问题。目标3将评估该角色 CD36在单核/巨噬细胞生物学中的研究进展 这是一种不表达CD36的转基因小鼠模型。 这个项目的完成将增加对早期 导致动脉粥样硬化的事件并允许开发新的治疗方法 通过特定阻断氧化低密度脂蛋白-巨噬细胞相互作用的策略。 此外，了解内化和细胞内 由CD36完成的信号转导可能会导致对 细胞功能。动物模型也可能用于测试 氧化剂和抗氧化剂在动脉粥样硬化形成中的作用。

CD36 is a multifunctional 88kD transmembrane glycoprotein expressed on platelets, monocytes, macrophages, certain specialized epithelial cells, and adipocytes. It has been shown to function as a cellular receptor for thrombospondin (TSP) and has recently been implicated as a macrophage scavenger receptor for oxidized low density lipoprotein (OxLDL). Oxidation of LDL is strongly linked to the pathogenesis of atherosclerosis in that lipid accumulation in atheromatous plaque results directly from internalization of OxLDL by intimal macrophages. In addition, OxLDL interactions with vascular cells may result in cellular activation to a prothrombotic, proatherogenic phenotype. The central hypothesis of this proposal is that CD36 is a major macrophage receptor for binding and internalizing ligands, including TSP and OxLDL. The focus will be to define the molecular basis of CD36 function and to probe its role in atherosclerosis. Studies in specific aim l will define structure-function relationships that govern CD36 receptor-ligand binding. Interactions with TSP and Oxidized LDL will be studies. These experiments will utilize recombinant CD36 peptides and solid phase and cellular binding studies. Specific aim 2 will define the mechanisms by which human macrophage CD36 internalizes ligands. Regulation of macrophage CD36 mRNA synthesis and surface protein expression in response to mediators of atherogenesis and differentiation will be studied using RNAse protection assays and immunomicroscopy. CD36-mediated internalization pathways and structure-function relationships that govern internalization will also be probed. Aim 3 will evaluate the role of CD36 in monocyte/macrophage biology by developing and studying a murine model genetically engineered so as not to express CD36. Completion of this project will increase understanding of early atherogenic events and allow for the development of novel therapeutic strategies by specific blockade of OxLDL-macrophage interactions. Furthermore, understanding how internalization and intracellular signaling is accomplished by CD36 may lead to broader insight into cellular function. The animal model may also be useful in testing the role of oxidants and anti-oxidants in atherogenesis.