Molecular Analysis Of Neutrophil Activation By Chemoattr

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Abstract

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.