The scavenger receptor CD36 participates a diverse array of physiological processes. In addition to its role in recognition of oxidized low density lipoprotein (oxLDL), lipid accumulation and foam cell formation, the scavenger receptor functions of CD36 have been linked to recognition of senescent and apoptotic cells, and the delivery of ligands within oxLDL into cells, such as ones for the nuclear hormone transcription factor PPAR-gamma. While studies thus far reported have shown that the primary ligands on oxLDL for CD36 are contained within the lipid portion of the particle, the structural nature of the lipids that support high affinity binding have not been characterized. In preliminary studies we have recently identified a novel family of oxidized choline glycerophospholipids that serve as high affinity ligands for CD36 (oxPC-CD36). Our preliminary studies suggest that these species may serve as major participants in CD36-dependent recognition of oxLDL by macrophages. Similarly, preliminary studies suggest that oxPC-CD36 and their phosphatidyl serine (PS) analogs (oxPS-CD36), contribute to CD36-mediated recognition of senescent or apoptotic cells. However, little is known about the structural and biochemical factors involved in formation of these species, or CD36-lipid ligand interactions. Moreover, the (patho)physiological relevance of this novel family of bioactive phospholipid oxidation products has not yet been examined. The overall goals of this proposal are to define the structures, biochemical properties, mechanisms of formation, critical receptor-ligand interactions, and physiological relevance, of specific oxidized phospholipid ligands of CD36.
The Specific Aims are: 1) To identify endogenous phospholipid oxidation products that serve as high affinity ligands for the macrophage scavenger receptor CD36 and define critical structure-function relationships for specific oxidized phospholipids and lipid- receptor complexes implicated in atherogenesis. 2) To examine the physiological relevance of specific oxidized phospholipid ligands for CD36 and define pathways through which leukocyte-generated oxidants participate in their formation in vivo.
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