CD36 is a member of the scavenger receptor family of pattern recognition receptors that are believed to have evolved with the innate immune system. CD36 binds a broad variety of ligands, including oxidized low density lipoprotein, thrombospondin- 1, malarial peptides, and apoptotic cells. Through binding of these ligands, CD36 is involved in such diverse processes as atherogenesis, angiogenesis, malarial pathogenesis, and tissue homeostasis. Despite its identification more than a decade ago, the physiological events regulated by CD36 ligation remain largely unknown. There is growing evidence to suggest that CD36 initiates cellular signaling, however the mechanism of this initiation, and the signal transduction pathways induced, are largely undefined. We now have evidence that beta-amyloid, a peptide central to the pathogenesis of Alzheimer's Disease, binds to CD36 and initiates activation of pro-inflammatory kinase pathways. Thus, Alzheimer's Disease might be added to the growing list of diseases whose pathogenesis may be modulated by CD36 signaling. Given its importance in two of the primary diseases associated with aging, atherogenesis and Alzheimer's Disease, understanding the mechanism of CD36 signaling is important. We propose to: (a) delineate the macrophage/microglial signaling cascade initiated by ligand binding of CD36, (b) identify the structural components of CD36 responsible for this signaling and (c) determine how CD36 signaling alters gene expression. These experiments will contribute to our understanding of how CD36 functions, and may provide important insights into its contribution to atherogenesis and Alzheimer's disease. A long term goal of these aims is to identify ways in which CD36 signaling might be abrogated, which may facilitate the identification of therapeutics designed to interrupt inflammatory signaling by CD36.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Pathology A Study Section (PTHA)
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Fuldner, Rebecca A
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Massachusetts General Hospital
United States
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