Molecular Analysis Of Neutrophil Activation

该项目的目的是确定血液白细胞迁移到炎症或感染的特定组织部位的分子机制。我们关注的是介导这一过程的化学引诱蛋白，并已经确定了部署在白细胞细胞表面的化学引诱受体大家族的成员。我们还发现了由病毒（包括疱疹病毒、痘病毒和艾滋病毒）制造的多种化学引诱剂和化学引诱剂受体模拟物的成员。我们将基因组学、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。一个主要目标是确定个体化学引诱剂和化学引诱剂受体的特定疾病关联，以确定潜在的新治疗靶点。为此，在2005年，我们开发了西尼罗病毒感染的小鼠模型，发现趋化因子受体和主要的HIV辅助受体CCR5对于协调白细胞向大脑的运输至关重要，这有助于病毒清除和小鼠存活。这为西尼罗河病毒的发病机制提供了新的见解，并提出了一个治疗问题，即目前正在开发用于治疗艾滋病毒/艾滋病患者的阻断CCR5的药物是否会导致这些患者对严重西尼罗河病毒感染的易感性增加。我们还进一步分析了之前关于动脉粥样硬化发病机制的炎症假说，并在Framingham心脏研究中发现趋化因子MCP-1基因的遗传变异与循环MCP-1水平升高和心肌梗死相关。这加强了趋化因子在将白细胞募集到这种疾病的血管壁中很重要的观点，并表明MCP-1是一个潜在的治疗靶点。我们还通过发现趋化因子受体CX3CR1的表达通过选择性NFAT1和nfat2依赖机制受到γ -c细胞因子IL-15和IL-2的相反调节，继续进一步了解其生物学特性。这表明响应IL-15而扩增的细胞产物可能会削弱其运输到富含CX3CR1配体CX3CL1的身体部位的能力。

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.