Molecular Analysis Of Neutrophil Activation By Chemoattr

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。我们使用基因组学、分子生物学、细胞生物学和流行病学，并与病毒学家合作，作为分析这些分子的主要方法。前几年解决并在2002财政年度继续解决的一个主要问题是确定个别化学引诱剂和化学引诱剂受体的特定疾病关联，以便确定潜在的新治疗靶点。在这方面，我们发现趋化因子受体CCR5的失活变体CCR5D32与肾移植排斥风险增加高度相关。这一初步结果虽然在统计上很有力，但需要在独立队列和研究中得到证实，以确定精确的机制。同样在2002年，我们研究了趋化受体FPRL1在体外结合淀粉样蛋白（阿尔茨海默病（AD）的主要病理蛋白）在AD发病中的作用。到目前为止，我们还没有发现FPRL1基因的遗传多态性，从而评估FPRL1与人群中AD的联系。相反，我们意外地发现了24个相关受体FPR的常见变体。这意味着这两种受体经历了不同的选择压力。为了进一步验证FPRL1/AD假说，需要新的工作来评估FPRL1调控区域的多态性。在2002财年，我们还发现spinorphin，一种具有抗炎特性的内源性阿片类物质，作为FPR的特异性拮抗剂。这是首次发现的内源性化学引诱受体拮抗剂之一，表明这些受体的负调控可能是控制炎症反应的重要方法。

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, and collaborations with virologists, as the principle methods for analyzing these molecules. A major question addressed in previous years and continued in FY2002 is to identify specific disease associations of individual chemoattractant and chemoattractant receptors, in order to identify potential new therapeutic targets. In this regard, we have found that CCR5D32, an inactive variant of the chemokine receptor CCR5, is highly associated with increased risk of renal transplant rejection. This preliminary result, although statistically strong, will require confirmation in independent cohorts as well as studies to define a precise mechanism. Also in FY2002, we investigated the hypothesis that the chemotactic receptor FPRL1 which in vitro binds amyloid beta, the major pathologic protein in Alzheimer's Disease (AD), functions in AD pathogenesis. So far we have not found a genetic polymorphism in the FPRL1 gene with which to evaluate FPRL1 linkage to AD in populations. In contrast, we unexpectedly found 24 common variants of the related receptor FPR. This implies that these two receptors have undergone distinct selective pressures. New work will be needed to assess polymorphism in the regulatory regions of FPRL1 to further test the FPRL1/AD hypothesis. In FY2002, we also discovered that spinorphin, an endogenous opioid with anti-inflammatory properties, acts as a specific antagonist at FPR. This is one of the first endogenous antagonists found for a chemoattractant receptor, and suggests that negative regulation of these receptors may be an important method for controlling the inflammatory response.