Molecular Analysis Of Neutrophil Activation By Chemoattr

这个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。我们一直专注于介导这一过程的趋化蛋白，并鉴定了部署在白细胞表面的趋化受体大家族的成员。这些受体是一个更大的受体家族的成员，这些受体都激活细胞内的G蛋白，作为细胞激活的第二步。我们还鉴定了由病毒制造的一组不同的趋化物质和趋化物质受体模拟物的成员，其中许多病毒会感染人类。我们使用基因组学、分子生物学、细胞生物学和流行病学，以及与病毒学家的合作，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.CX3CR1受体的一个多态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。这项工作为这些疾病的发病机制提出了新的分子机制，并指出CX3CR1是一个潜在的治疗靶点。2.Kaposi肉瘤相关疱疹病毒HHV8编码的一种受体ORF74可与人趋化素型趋化因子结合，可结构性地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。这项工作统一了卡波西？S肉瘤发病机制的感染和生长因子理论，并支持了其他人发表的关于该受体可能是卡波西肉瘤良好治疗靶点的工作。3.一种名为FPRL1的趋化受体可以介导白细胞对淀粉样β蛋白的趋化和氧化剂的产生，淀粉样β蛋白是阿尔茨海默病患者老年斑中的主要病理蛋白。这项工作为阿尔茨海默病中发现的炎症反应提出了一种新的分子机制，并指出FPRL1是一个潜在的治疗靶点。

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.