Recently, CD36, a protein previously characterized as an adhesion molecule, has been shown to be an active transporter of long chain fatty acids, and to play a role in the recognition and uptake of apoptotic cells and shed photoreceptor outer segments. The central premise of this application is that CD36 plays an essential role as a scavenger receptor on monocytes/macrophages and in the specialized epithelium of the retina, and functions as a long chain fatty acid transporter in muscle and adipocytes. The investigators have used targeted homologous recombination to disrupt the CD36 gene in mice. The loss of CD36 is not lethal, but may predispose the animal to tissue damage at times of stress, injury, and overwhelming infection. To this end, they will confirm that these mice are null with respect to CD36 protein and function, and then use them as a model to confirm the hypothesis that CD36-mediated scavenger function is important in normal homeostasis in the context of recognition and uptake of apoptotic cells, which arise through aging, during wound healing, and in inflammatory situations. They will use these mice as a model to study the consequences of the deletion of a long chain fatty acid transporter in lipid storage and metabolism. Finally, they hypothesize that the loss of CD36 may speed progression of eye disease in a constant illumination model.
The Specific Aims are 1) characterization of CD36-null mice, 2) characterization of the role of CD36 as a scavenger receptor, and 3) characterization of the role of CD36 in fatty acid metabolism.
|Febbraio, M; Guy, E; Coburn, C et al. (2002) The impact of overexpression and deficiency of fatty acid translocase (FAT)/CD36. Mol Cell Biochem 239:193-7|
|Bodart, V; Febbraio, M; Demers, A et al. (2002) CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res 90:844-9|
|Febbraio, M; Hajjar, D P; Silverstein, R L (2001) CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest 108:785-91|
|Simantov, R; Febbraio, M; Crombie, R et al. (2001) Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1. J Clin Invest 107:45-52|
|Husemann, J; Obstfeld, A; Febbraio, M et al. (2001) CD11b/CD18 mediates production of reactive oxygen species by mouse and human macrophages adherent to matrixes containing oxidized LDL. Arterioscler Thromb Vasc Biol 21:1301-5|
|Podrez, E A; Febbraio, M; Sheibani, N et al. (2000) Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J Clin Invest 105:1095-108|
|Coburn, C T; Knapp Jr, F F; Febbraio, M et al. (2000) Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem 275:32523-9|
|Febbraio, M; Abumrad, N A; Hajjar, D P et al. (1999) A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism. J Biol Chem 274:19055-62|