Neutrophil interactions with intestinal epithelial cells

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DESCRIPTION (provided by applicant): Response to Notice Number (NOT-OD-09-058), Notice Title: NIH Announces the Availability of Recovery Funds for Competitive Revision Applications. The etiology of human inflammatory bowel disease (IBD) includes both aberrant leukocyte responses and epithelial barrier dysfunction. Junctional Adhesion Molecule (JAM) family of proteins have been shown to regulate both epithelial tight junction function and leukocyte transmigration. Our results suggest that JAM proteins play an important role in the pathophysiology of intestinal mucosal inflammation such as observed in IBD. JAM-A is the best characterized family member to date, but in-vivo studies of JAM-A function have been limited and the results often contradictory. One difficulty has been determining the role of JAM-A on multiple cell types potentially contributing to observed phenotypes. Focused experiments employing bone marrow chimeras and relevant disease models alongside complementary in vitro systems will provide the means to dissect the important contributions of epithelial and leukocyte JAM-A to mucosal permeability and intestinal inflammation. Our preliminary results suggest an important role for JAM-A in regulation of PMN recruitment in the intestine and detail findings consistent with compensatory B-cell hyperplasia that may protect these animals from developing spontaneous colitis in face of a large increase in colonic permeability. These observations suggest that JAM-A plays a central role in intestinal homeostasis by direct regulation of leukocyte function and by indirect means through regulation of permeability of the colonic epithelium. Further research extending these findings is clearly warranted and may significantly enhance our understanding of the relationship between JAMs and mucosal homeostasis and, more broadly, basic regulation of mucosal immune function. PUBLIC HEALTH RELEVANCE: Human inflammatory bowel disease (IBD) is characterized by both aberrant leukocyte responses and intestinal barrier dysfunction. Research focused on the contributions of junctional adhesion molecule-A (JAM-A) to mucosal permeability and intestinal inflammation should, therefore, be highly relevant in understanding pathophysiology of IBD and in the development of therapeutic targets to ameliorate intestinal inflammation.