MOLECULAR AND CELL BIOLOGY OF CD36 A TSP RECEPTOR

CD 36是一种多功能的88 kD跨膜糖蛋白 表达于血小板、单核细胞、巨噬细胞、某些专门的 上皮细胞和脂肪细胞。它被证明是一种 血小板反应蛋白（TSP）的细胞受体，最近已被 作为巨噬细胞清道夫受体， 密度脂蛋白（OxLDL）。LDL的氧化与 动脉粥样硬化发病机制中脂质积聚 动脉粥样硬化斑块直接由氧化低密度脂蛋白的内化引起， 内膜巨噬细胞此外，OxLDL与血管的相互作用 细胞可导致细胞活化为血栓前体， 致动脉粥样硬化表型这一提议的核心假设是 CD 36是一种主要的巨噬细胞受体， 内化配体，包括TSP和OxLDL。重点将是 确定CD 36功能的分子基础，并探讨其在 动脉粥样硬化在特定目标的研究l将定义结构-功能 控制CD 36受体-配体结合的关系。相互作用 与TSP和氧化低密度脂蛋白将进行研究。这些实验将 利用重组CD 36肽和固相和细胞结合 问题研究具体目标2将确定人类 巨噬细胞CD 36内化配体。巨噬细胞调节 CD 36 mRNA的合成和表面蛋白的表达 动脉粥样硬化形成和分化的介质将使用 RNA酶保护测定和免疫显微镜检查。CD 36介导 内化途径和结构-功能关系， 并将探讨治理内部化。目标3将评估 CD 36在单核细胞/巨噬细胞生物学中的作用 一种基因工程改造不表达CD 36的鼠模型。 该项目的完成将增加对早期 动脉粥样硬化事件，并允许开发新的治疗药物 通过特异性阻断OxLDL-巨噬细胞相互作用的策略。 此外，了解内化和细胞内 通过CD 36完成的信号传导可能会导致更广泛的了解 细胞功能该动物模型也可用于测试 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.