CONTINUING FACULTY (CARDIOVASCULAR DISEASE)

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SPECIFIC AIMS Role of glutamate in CXCR2-mediated neuroprotection against amyloid-beta neurotoxicity. Identification and characterization of CXCR4 interacting proteins that are potentially involved in chemokine receptor signaling and trafficking. SUMMARY The major of our research is the role of chemokine receptors (CXCR2 and CXCR4) interacting proteins in the receptor signaling, trafficking, and the receptor-mediated chemotaxis. These receptor functions are important for neurodevelopment and neurodegneration, cancer metastasis, and HIV infection. Our major findings in the past year are: 1) CXCR2-mediated neuroprotection is attenuated by NMDA. Exposure of neurons to NMDA induces phosphorylation and desensitization of CXCR2, and prevents CXCR2 recycling. These data suggest that NMDA-induced CXCR2 desensitization may play a role in its attenuation effects on CXCR2-mediated neuroprotection. These data have been published in Molecular Pharmacology (2005 Aug;68(2):528-37). 2) The heat shock cognate protein 73 (Hsc73) was identified to be a CXCR4 binding protein, which is important for CXCR4-mediated endocytosis and chemotaxis. These data have been published in Molecular Pharmacology (2006 Apr;69(4):1269-79). 3) Cortactin is a CXCR4 interacting protein, which is tyrosine phosphorylated by stimulation of CXCR4, and is involved in the receptor-mediated MAP kinase activation, the receptor internalization and recycling, and the receptor-mediated chemotaxis. These data have been submitted to Molecular and Cellular Biology. In addition, in collaboration with Dr. Ann Richmond, we published a review paper regarding chemokine receptor trafficking in Cytokine Growth Factor Rev (2005 Dec;16(6):637-58). We are invited by Current Pharmaceutical Design to write a review article entitled ¿Chemokine Receptor Interacting Proteins: Potential Targets for Alternative Cancer Therapies¿. This paper has been submitted. Based on the above results, we submitted the following two grants. 1) NIH Specified Neuroscience Research Program (SNRP) entitled ¿role of CXCR2 in amyloid-beta-induced neurodegeneration¿, which is now pending awarding; 2) VA Merit Review grant entitled¿ chemokine receptors and neurodegeneration¿, which is under reviewing.