Molecular Analysis Of Neutrophil Activation By Chemoattr

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Abstract

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.