Many inflammatory diseases of mucosal surfaces are characterized by transepithelial migration of neutrophils (PMN). Examples of such diseases are common in the gastrointestinal system (ulcerative colitis, Crohn's disease), respiratory tract (bronchial pneumonia, bronchitis), and urinary tract (pyelonephritis, cystitis). Accumulation of neutrophils within the lumenal spaces of these organs is associated with epithelial injury and correlates with disease symptoms. Despite a wealth of evidence supporting a central role of PMN in epithelial dysfunction in these diseases, the mechanism(s) of leukocyte interaction with mucosal remains poorly defined. In this proposal, our studies will focus on defining the molecular basis of leukocyte interactions with epithelial cells. Previously, we have shown that PMN transepithelial migration requires specific regions of the neutrophil beta2 integrin CD11b/CD18 and is independent of selectins and ICAM-1. Furthermore, we identified CD47 as an additional crucial component of the transepithelial migration response. However, the precise molecular details of these adhesive events and the nature of the epithelial counter- receptors for migrating PMN remain undefined. The overall goals of this proposal are to identify and characterize key adhesive interactions between neutrophils (PMN) and epithelial cells that serve to regulate the process of PMN transepithelial migration. Recently, a novel immunoglobulin superfamily member termed junction adhesion molecule (JAM) that is concentrated at cell-to-cell borders (intercellular junctions) of murine endothelium and epithelium was shown to participate in monocyte transmigration across mouse endothelium.
In Specific Aim 1, we will extend our primary characterizing of the human homolog of JAM to define its role in PMN interactions with epithelial cells.
In Specific aim 2, we will define the mechanism of how a novel epithelial mAb inhibits PMN migration and continue to produce others that inhibit the PMN transmigration response.
Specific aim 3 will focus on the identification of specific epithelial receptors for CD11b/CD18 using monoclonal antibodies. Lastly, Specific aim 4 will employ random peptide phage display to identify peptide ligands for CFD11b/CD18 that modulate PMN-epithelial adhesion, Information from these studies will lead to a better understanding of the molecular events involved in PMN interactions with epithelial cells and may provide new ideas for therapeutic strategies aimed at attenuating inflammatory diseases of mucosal surfaces.
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