The increased infiltration of inflammatory cells (neutrophils, lymphocytes, macrophages anddendritic cells) into the gastrointestinal tract is a hallmark of both ulcerative colitis andCrohn's disease. The recruitment of these leukocytes may be controlled in part by a familyof chemotactic cytokines, known as chemokines. We propose to investigate the functionalrole of chemokines in inflammatdry bowel disease and to examine if chemokine antagonismwill alleviate or block inflammatory bowel disease.Specifically we will:1) Define the functional contribution of chemokine receptors to IBD. We will definethe functional relevance of individual chemokine receptors to inflammatory bowel diseaseusing chemokine receptor knockout mice. Prioritization of target genes will be done on thebasis of documented expression of these receptors in human IBD samples and inexperimental models of IBD.2) Define the functional contribution of chemokine ligands to IBD. We will define thefunctional relevance of chemokine ligands to inflammatory bowel disease using chemokineligand knock-out mice. In addition, we will attempt to interfere with several chemokinenetworks at once. To this end we will use transgenic mice expressing the chemokine bindingprotein, M3.This work will provide insights on the role of chemokines in inflammatory bowel disease andwill examine the therapeutic potential of the chemokine blockade to IBD.
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