Identification and Regulation of Defensins in Human Mucosal Tissue

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As stated in our original application, given the new evidence that human (3 defensins (hBDs) are important immunomodulatory bridging agents between innate and adaptive immunity, it behooves us to understand the regulation of these peptides in a broad range of human mucosal tissue. Are they regulated the same in different mucosae? Are they regulated the same in various disease manifestations of epithelial tissue? To address these questions we will refine our knowledge of defensins with regard to their expression in various mucosae and to more closely examine the regulation of their expression within various mucosal sites. We therefore propose the following aims for this proposal: Specific Aim I. Conduct immunolocalization studies of hBD-2 and hBD-3 in healthy and diseased oral, skin and intestinal mucosae. ¿ Compare the immunolocalization of hBD-2 and hBD-3 in normal oral, gut and skin epithelium. ¿ Determine if defensin expression or localization changes within epithelial disease in the various mucosal tissue. Specific Aim II. Examine the regulatory mechanism for expression of hBD-2 and hBD-3 in oral, skin and intestinal epithelium and cells. ¿ Determine if primary and immortalized oral, gut and skin epithelial cells upregulate hBD-2 and hBD-3 in response to known inducers of defensin expression, including the combination of IL-22 and IL-17. Determine if the response of defensin upregulation is modified using primary cells obtained from tissue disorders for the respective mucosae (eg, Pemphigus, IBD, hyperkeratosis). ¿ Examine expression and co-localization of natural defensin-inducing agents (eg, EGF, TGFa, IGF-1) using immunohistochemical analysis. ¿ Determine the regulation of hBD-2 and -3 expression by proinflammatory TLR-agonists and immune cytokines by intestinal epithelial cells.