A major component of many inflammatory diseases of mucosal surfaces, particularly in the intestine, ismigration of large numbers of neutrophils (PMN) across the epithelium and accumulation within a lumen. Insuch conditions, disease symptoms are complex but directly related to leukocyte effects on the epithelialbarrier and epithelial cell function. While much has been learned about mechanisms of leukocyte emigrationfrom the circulation, much less is known about the receptors that regulate leukocyte interactions with theintestinal epithelium. Over the past several years, evidence has emerged linking a family of adhesion proteinstermed Junctional Adhesion Molecules (JAMs) as important regulators of leukocyte trafficking and barrierfunction that is consistent with the differential expression of JAMs in populations of leukocytes and epithelialtight junctions. Our studies suggest that expression of the prototypic family member termed JAM-A onleukocytes and epithelial cells is important in preventing pathologic inflammation in the intestine. Furthermore,our recent findings have implicated other JAM-like proteins in mediating transepithelial migration (TEM) ofneutrophils in the intestine; however, much less is known about these JAMs. The overall goal of this proposalis to define the role of JAMs in regulating intestinal inflammation by evaluating contributions of leukocyte andepithelial expressed proteins. We will specifically examine effects of JAM-A deficiency on innate immunefunction and accompanying adaptive immune responses in the intestine. In addition, we will explore the rolesof other closely related JAMs in the regulation of neutrophil TEM and barrier function. In addition to gaininginsights into the complex molecular basis of the relationship between the intestinal epithelial barrier andspecific innate/adaptive immune cell components, it is hoped that these studies will provide new ideas for thedevelopment of agents that alter JAM protein function for use as immunomodulatory agents, to manipulatebarrier function for drug/vaccine delivery, or cancer therapy.
A characteristic feature of a number of diseases of the gastrointestinal; respiratory; and urinary systems isexcessive recruitment and migration of acute inflammatory cells termed neutrophils across a specializedepithelium that lines these organs to form a protective barrier. Proteins that regulate the epithelial barriertermed JAMs have also been shown to play roles in the recruitment and migration of neutrophils; yet themechanisms linking these disparate JAM functions are not understood. This proposal seeks to characterize therole a prototypic JAM protein termed JAM-A and two related molecules in regulating neutrophil migration in theintestine and the role these proteins play in maintenance of the protective barrier. Understanding therelationships between JAM proteins; epithelial barrier; and inflammation may provide new strategies for organtargeted therapies with a potential benefit of less systemic side effects than those currently available forconditions such as inflammatory bowel disease.
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