NOVEL SCAVENGER RECEPTOR IN MACROPHAGE FOAM CELL

氧化低密度脂蛋白(OxLDL)与 动脉粥样硬化的发病机制和作为血管细胞的激动剂， 包括单核细胞、血小板和内皮细胞。几个 参与结合和内化修饰的细胞受体 低密度脂蛋白颗粒已被发现，并被命名为~清道夫 受体~。尽管他们可能在这方面扮演着重要角色 动脉粥样硬化性泡沫细胞发育的相对重要性 这些受体中的每一个都能将脂蛋白结合到 体内巨噬细胞及其分子机制 氧化低密度脂蛋白颗粒进入巨噬细胞并激活细胞， 不完全理解。细菌的鉴定和表征 因此，氧化低密度脂蛋白的细胞受体对于理解泡沫至关重要 细胞的形成和动脉粥样硬化的形成，并形成了这一过程的基础 项目。CD36是一种88kD的跨膜糖蛋白，表达 在血小板、单核细胞、巨噬细胞、某些特殊的上皮细胞上 细胞和脂肪细胞。它最近被牵连为一名 单核细胞氧化低密度脂蛋白的清道夫受体。中心假说 CD36是一种主要的巨噬细胞受体 结合和内化氧化低密度脂蛋白。我们建议评估它的作用 在动脉粥样硬化方面。在具体目标1中，我们将定义 人巨噬细胞CD36内化机制的研究 氧化低密度脂蛋白，评估CD36表面表达的调节和 确定细胞外关系(共受体)和细胞内关系 调控CD36介导的内化的事件(细胞激活) 和信号。在具体目标2中，我们将评估结构功能 CD36-OxLDL结合中涉及的关系，表征 与CD36结合并映射CD36结构域的OxLDL的组成(S) 结合OxLDL的CD36。在具体目标3中，我们将解决 动物模型中氧化低密度脂蛋白与CD36结合的活体相关性 动脉粥样硬化，确定清道夫的时间表达 动物和人类动脉粥样硬化病变中的受体及其评价 小鼠动脉粥样硬化的发生发展 动脉粥样硬化的基因工程模型不能表达 CD36(CD36~基因敲除~)。该项目的完成将 演示CD36在人类免疫缺陷中的作用和相对重要性 与先前表征的氧化受体的关系 脂蛋白。氧化低密度脂蛋白表位的鉴定 CD36相关区域的结合和鉴定 氧化低密度脂蛋白的结合将允许开发新的策略 抑制氧化的脂蛋白的结合和摄取 动脉硬化。此外，该项目的范围是 足够广泛，足以定义内化事件和细胞内 当OxLDL与CD36结合时发生的信号传递过程，以及 导致对促炎和亲炎的更广泛的见解 氧化低密度脂蛋白引发的动脉粥样硬化激活事件。

Oxidized low density lipoprotein (OxLDL) is strongly implicated in the pathogenesis of atherosclerosis and as agonist for vascular cells, including monocytes, platelets and endothelial cells. Several cellular receptors involved in binding and internalizing modified LDL particles have been identified and are termed ~scavenger receptors~. Although they presumably have a significant role in atherosclerotic foam cell development, the relative importance of each of these receptors in incorporating lipoproteins into macrophages in vivo and the molecular mechanisms by which OxLDL particles enter macrophages and activate cells, remain incompletely understood. Identification and characterization of cellular receptors for OxLDL is thus crucial to understanding foam cell formation and atherogenesis, and forms the basis of this project. CD36 is an 88 kD transmembrane glycoprotein expressed on platelets, monocytes, macrophages, certain specialized epithelial cells, and adipocytes. It has recently been implicated as a monocyte 'scavenger' receptor for OxLDL. The central hypothesis of this proposal is that CD36 is a major macrophage receptor for binding and internalizing OxLDL. We propose to evaluate its role in atherosclerosis. In specific aim 1, we will define the mechanisms by which human macrophage CD 36 internalizes OxLDL, evaluate the regulation of CD36 surface expression and determine extracellular relationships (co-receptors) and intracellular events (cell activation) that govern CD36 mediated internalization and signaling. In specific aim 2, we will evaluate structure-function relationships involved in CD36-OxLDL binding, characterize the components of OxLDL that bind CD 36 and map the domain(s) of CD36 that bind OxLDL. In specific aim 3, we will address the vivo relevance of the binding of OxLDL to CD36 in animal models of atherosclerosis, determine the temporal expression of scavenger receptors in animal and human atherosclerotic lesions and evaluate the development and progression of atherosclerosis in a murine model of atherosclerosis genetically engineered so a not to express CD36 (CD36 ~knockout~). Completion of this project will demonstrate the function and relative importance of CD36 in relation to previously characterized receptors for oxidized lipoproteins. Characterization of OxLDL epitopes necessary for binding and identification of regions of CD36 which are involved in OxLDL binding will allow for the development of novel strategies to inhibit the binding and uptake oxidized lipoproteins during atherosclerosis. Furthermore, the scope of the project is sufficiently broad to define internalization events and intracellular signaling processes that occur when OxLDL binds to CD36, and lead to broader insights into pro-inflammatory and pro- atherosclerotic activation events initiated by OxLDL.