The human intestine is lined by a single layer of protective epithelial cells, which possess properties such as barrier and ion transport functions. In addition, the epithelium functions as a component of the innate immune system, including expression of functional antimicrobial peptides. Recent studies from our laboratory indicate that intestinal epithelial cells express the anti-infective molecule bactericidal permeability-increasing protein (BPI), a peptide with potent antimicrobial and endotoxin-neutralizing activity. Preliminary studies for this application indicate that: a) intestinal epithelial BPI is functionally important in regulating epithelial responses to endotoxin; b) that bacterial-derived products can regulate epithelial expression of BPI; and c) that the murine homolog of BPI is expressed on intestinal epithelia. In the proposed studies we will systematically define activation pathways of epithelial BPI production and define regulatory pathways both in vitro and in vivo. Parallel experiments will be done utilizing epithelial cell lines and native human intestinal tissue to define these principles. First, we will elucidate the basis of epithelial BPI production. Using molecular, morphologic and functional readouts, we will elucidate molecular pathways of epithelial BPI expression. Second, we will define the role of epithelial BPI in murine colitis. Third, we will profile the expression patterns of epithelial BPI protein and mRNA in patients with linflammatory bowel disease (IBD). Successful completion of the Aims outlined in this application will yield insight into the role of endogenous antimicrobial peptides in the pathogenesis of IBD and will provide I predictive value for future development of experimental therapeutics for such disorders.

R21DK065768

2004-06-01

2007-05-31