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.
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