A major component of many inflammatory diseases of mucosal surfaces, particularly in the intestine, is migration of large numbers of neutrophils (PMN) across the epithelium and accumulation within a lumen. In such conditions, disease symptoms are complex but directly related to leukocyte effects on the epithelial barrier and epithelial cell function. While much has been learned about mechanisms of leukocyte emigration from the circulation, much less is known about the receptors that regulate leukocyte interactions with the intestinal epithelium. Over the past several years, evidence has emerged linking a family of adhesion proteins termed Junctional Adhesion Molecules (JAMs) as important regulators of leukocyte trafficking and barrier function that is consistent with the differential expression of JAMs in populations of leukocytes and epithelial tight junctions. Our studies suggest that expression of the prototypic family member termed JAM-A on leukocytes 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) of neutrophils in the intestine;however, much less is known about these JAMs. The overall goal of this proposal is to define the role of JAMs in regulating intestinal inflammation by evaluating contributions of leukocyte and epithelial expressed proteins. We will specifically examine effects of JAM-A deficiency on innate immune function and accompanying adaptive immune responses in the intestine. In addition, we will explore the roles of other closely related JAMs in the regulation of neutrophil TEM and barrier function. In addition to gaining insights into the complex molecular basis of the relationship between the intestinal epithelial barrier and specific innate/adaptive immune cell components, it is hoped that these studies will provide new ideas for the development of agents that alter JAM protein function for use as immunomodulatory agents, to manipulate barrier function for drug/vaccine delivery, or cancer therapy.
A characteristic feature of a number of diseases of the gastrointestinal, respiratory, and urinary systems is excessive recruitment and migration of acute inflammatory cells termed neutrophils across a specialized epithelium that lines these organs to form a protective barrier. Proteins that regulate the epithelial barrier termed JAMs have also been shown to play roles in the recruitment and migration of neutrophils, yet the mechanisms linking these disparate JAM functions are not understood. This proposal seeks to characterize the role a prototypic JAM protein termed JAM-A and two related molecules in regulating neutrophil migration in the intestine and the role these proteins play in maintenance of the protective barrier. Understanding the relationships between JAM proteins, epithelial barrier, and inflammation may provide new strategies for organ targeted therapies with a potential benefit of less systemic side effects than those currently available for conditions such as inflammatory bowel disease.
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