Molecular Analysis Of Neutrophil Activation By Chemoattr

该项目的主要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。这些受体是一个更大的受体家族的成员，它们都激活细胞内G蛋白，作为细胞激活的第二步。我们还确定了由病毒产生的多种化学引诱剂和化学引诱剂受体模拟物的成员，其中许多病毒感染人类。我们利用基因组学、分子生物学、细胞生物学和流行病学，以及与病毒学家合作，作为分析这些分子的主要方法。在2001财政年度，该项目取得的最重要进展如下。1. 受体CX3CR1的多态性变异是艾滋病和动脉粥样硬化性冠状动脉疾病的遗传危险因素。这项工作提示了这些疾病发病机制的新分子机制，并指出CX3CR1是一个潜在的治疗靶点。2. 一种名为ORF74的受体，由卡波西氏肉瘤相关疱疹病毒HHV8编码，可结合人趋化因子型趋化因子，可组成性激活促炎基因转录激活因子NF-kB，诱导促炎细胞因子、趋化因子和生长因子基因表达。这项工作将卡波西的感染和生长因子理论结合起来。这一发现支持了前人的研究成果，表明该受体可能是卡波西氏肉瘤的一个很好的治疗靶点。3. 一种名为FPRL1的趋化受体可以介导白细胞趋化和氧化剂产生，以响应淀粉样蛋白- β，淀粉样蛋白是阿尔茨海默病患者老年斑中发现的主要病理蛋白。这项工作提示了阿尔茨海默病炎症反应的一种新的分子机制，并指出FPRL1是一种潜在的治疗靶点。

The primary purpose 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. These receptors are members of a much larger family of receptors that all activate intracellular G proteins as the second step in cell activation. We have also identified members of a diverse group of chemoattractant and chemoattractant receptor mimics made by viruses, many of which infect man. We use genomics, molecular biology, cell biology and epidemiology, as well as collaboration with virologists, as the principle methods for analyzing these molecules. In fiscal year 2001, the most important advances made in this project were as follows. 1. A polymorphic variant of the receptor CX3CR1 is a genetic risk factor for both AIDS and atherosclerotic coronary artery disease. This work suggests new molecular mechanisms for the pathogenesis of these diseases, and points to CX3CR1 as a potential therapeutic target. 2. A receptor named ORF74, which is encoded by the Kaposi's sarcoma-associated herpesvirus HHV8 and can bind human chemokine-type chemoattractants, can constitutively activate the pro-inflammatory gene transcription activator NF-kB and induce pro-inflammatory cytokine, chemokine and growth factor gene expression. This work unifies the infectious and growth factor theories of Kaposi?s sarcoma pathogenesis, and supports previous work published by others suggesting that this receptor may be a good therapeutic target for Kaposi's sarcoma. 3. A chemoattractant receptor named FPRL1 can mediate leukocyte chemotaxis and oxidant production in response to amyloid-beta, the major pathologic protein found in senile plaques of patients with Alzheimer's Disease. This work suggests a new molecular mechanism for the inflammatory reaction found in Alzheimer's Disease and points to FPRL1 as a potential therapeutic target.