CONTINUING FACULTY (CARDIOVASCULAR DISEASE)

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。谷氨酸在cxcr2介导的抗淀粉样蛋白神经毒性的神经保护中的作用。可能参与趋化因子受体信号传导和运输的CXCR4相互作用蛋白的鉴定和表征。我们的主要研究方向是趋化因子受体（CXCR2和CXCR4）相互作用蛋白在受体信号传导、运输和受体介导的趋化性中的作用。这些受体的功能对神经发育和神经变性、癌症转移和HIV感染都很重要。我们在过去一年的主要发现是：1)cxcr2介导的神经保护作用被NMDA减弱。神经元暴露于NMDA诱导CXCR2的磷酸化和脱敏，并阻止CXCR2的再循环。这些数据表明，nmda诱导的CXCR2脱敏可能在其对CXCR2介导的神经保护的衰减作用中发挥作用。这些数据已发表在Molecular Pharmacology （2005 Aug;68(2):528-37）上。2)热休克同源蛋白73 （Hsc73）被鉴定为CXCR4结合蛋白，在CXCR4介导的内吞噬和趋化过程中起重要作用。这些数据发表在分子药理学杂志（2006年4月；69(4):1269-79）。3)皮质蛋白是一种CXCR4相互作用蛋白，通过CXCR4的刺激使酪氨酸磷酸化，参与受体介导的MAP激酶活化、受体内化和再循环以及受体介导的趋化作用。这些数据已提交给分子与细胞生物学。此外，我们与Ann Richmond博士合作，在细胞因子生长因子Rev （2005 Dec;16(6):637-58）上发表了一篇关于趋化因子受体转运的综述论文。我们受《当前药物设计》的邀请撰写了一篇题为《趋化因子受体相互作用蛋白：替代癌症治疗的潜在靶点》的综述文章。这篇论文已经提交。基于以上结果，我们提交了以下两项资助。1) NIH指定神经科学研究计划（SNRP）题为“CXCR2在淀粉样蛋白- β诱导的神经变性中的作用”，目前正在等待授予；2)“趋化因子受体和神经退行性变”的VA优秀评审基金，正在审查中。

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.