NOVEL SCAVENGER RECEPTOR IN MACROPHAGE FOAM CELL

氧化型低密度脂蛋白（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 参与结合和内化修饰的细胞受体 低密度脂蛋白颗粒已被确定，并被称为~清道夫 受体~。 尽管他们可能在 动脉粥样硬化泡沫细胞发育的相对重要性 这些受体中的每一种都参与了脂蛋白的整合， 巨噬细胞在体内和分子机制， OxLDL颗粒进入巨噬细胞并激活细胞， 不完全理解。 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 细胞形成和动脉粥样硬化，并形成了基础， 项目 CD 36是一种88 kD的跨膜糖蛋白， 血小板、单核细胞、巨噬细胞、某些特定的上皮细胞 细胞和脂肪细胞。 它最近被牵连为一个 氧化低密度脂蛋白的单核细胞清道夫受体。 核心假设 这一建议的一个重要原因是，CD 36是一种主要的巨噬细胞受体， 结合和内化OxLDL。 我们建议评估其作用 动脉粥样硬化。 在具体目标1中，我们将定义 人巨噬细胞CD 36内化的机制 OxLDL，评估CD 36表面表达的调节， 确定细胞外关系（共受体）和细胞内 控制CD 36介导的内化的事件（细胞活化） 和信号。 在具体目标2中，我们将评估结构-功能 参与CD 36-OxLDL结合的关系，表征了 结合CD 36并映射 结合OxLDL的CD 36。 在具体目标3中，我们将解决 在动物模型中OxLDL与CD 36结合的体内相关性 动脉粥样硬化，确定清道夫的时间表达 受体在动物和人类动脉粥样硬化病变中的作用，并评估 小鼠动脉粥样硬化的发生和发展 动脉粥样硬化的基因工程模型， CD 36（CD 36 ~敲除~）。 该项目的完成将 证明了CD 36的功能和相对重要性 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表征 结合和鉴定CD 36的区域，这些区域参与 OxLDL结合将允许开发新的策略 以抑制氧化脂蛋白的结合和摄取， 动脉粥样硬化 此外，该项目的范围是 足够宽泛以定义内化事件和细胞内 当OxLDL与CD 36结合时发生的信号传导过程，以及 导致对促炎和促炎的更广泛的见解， OxLDL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.