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