Molecular Analysis Of Neutrophil Activation

该项目的目的是确定血液白细胞迁移到发炎或感染的特定组织部位的分子机制。我们已经集中在介导这一过程的趋化蛋白，并确定了一个大家族的趋化受体，部署在白细胞表面的成员。我们还鉴定了由病毒（包括疱疹病毒、痘病毒和HIV）产生的不同化学引诱物和化学引诱物受体模拟物。我们使用基因组学、分子生物学、细胞生物学和流行病学作为分析这些分子的主要方法。一个主要的目标是确定具体的疾病协会个别化学引诱物和化学引诱物受体，以确定潜在的新的治疗靶点。为此，在2005财年，我们开发了西尼罗河病毒感染的小鼠模型，并发现趋化因子受体和主要的HIV辅助受体CCR 5对于协调白细胞运输到大脑至关重要，这有助于病毒清除和小鼠存活。这为WNV的发病机制提供了新的见解，并提出了一个治疗问题，即阻断CCR 5的药物（目前正在开发用于治疗HIV/AIDS患者）是否可能导致这些患者对严重WNV感染的易感性增加。我们还跟进了我们以前对动脉粥样硬化发病机制的炎症假说的分析，并发现趋化因子MCP-1基因的遗传变异与循环MCP-1水平增加和心肌梗死相关。这加强了趋化因子在这种疾病中将白细胞募集到血管壁中的重要性的概念，并表明MCP-1作为潜在的治疗靶点。我们还继续进一步了解趋化因子受体CX 3CR 1的生物学，我们发现其表达通过选择性NFAT 1和NFAT 2依赖性机制由γ-c细胞因子IL-15和IL-2反向调节。这表明响应于IL-15而扩增的细胞产物可能在其运输到富含CX 3CR 1配体CX 3CL 1的身体部位的能力方面受损。

The aim of this project is to define the molecular mechanisms by which blood leukocytes migrate to specific tissue sites that are inflamed or infected. We have focused on chemoattractant proteins that mediate this process and have identified members of a large family of chemoattractant receptors that are deployed on the leukocyte cell surface. We have also identified members of a diverse group of chemoattractant and chemoattractant receptor mimics made by viruses, including herpesviruses, poxviruses and HIV. We use genomics, molecular biology, cell biology and epidemiology as the principle methods for analyzing these molecules. A major goal is to identify specific disease associations of individual chemoattractant and chemoattractant receptors, in order to identify potential new therapeutic targets. To this end, in FY05 we developed a mouse model of West Nile Virus infection and discovered that the chemokine receptor and major HIV coreceptor CCR5 is critical for coordinating leukocyte trafficking to the brain, which facilitates viral clearance and mouse survival. This provides new insight into the pathogenesis of WNV, and raises a therapeutic concern about whether agents that block CCR5, which are now being developed for treatment of patients with HIV/AIDS, might induce increased susceptibility to severe WNV infection in these patients. We have also followed up our previous analysis of the inflammation hypothesis of atherosclerosis pathogenesis, and discovered that genetic variants of the chemokine MCP-1 gene are associated with increased circulating MCP-1 levels and myocardial infarction in the Framingham Heart Study. This strengthens the notion that chemokines are important in recruiting leukocytes to the vessel wall in this disease, and suggests MCP-1 as a potential therapeutic target. We have also continued to further understanding of the biology of the chemokine receptor CX3CR1 through our finding that its expression is oppositely regulated by the gamma-c cytokines IL-15 and IL-2 via selective NFAT1- and NFAT2-dependent mechanisms. This suggests that cell products expanded in response to IL-15 may be crippled in their ability to traffic to body sites rich in the CX3CR1 ligand CX3CL1.