The emergence of antibiotic-resistant microorganisms has heightened interest in the study of endogenous antimicrobial substances and the mechanisms regulating their expression in humans. Defensins are cysteine-rich cationic peptides isolated from several mammals, including humans, with broad-spectrum antimicrobial activity. The intestinal epithelium is a surface in continual contact with luminal contents variably laden with microbes, yet infection is uncommon. The investigator proposes that epithelial defensins, which can be grouped into two distinct structural subfamilies, designated alpha- and beta-, contribute to antimicrobial defense of the enteric mucosa. Furthermore, he proposes that there is a different strategic utilization of these two subfamilies of defensins in the small intestine and colon, in terms of structure/function, anatomical patterns of expression and types of regulation. The investigator suggests that these differences have evolved to accomplish host defense in these two very different environments. To address these hypotheses, the investigator proposes to isolate and structurally characterize the predominant defensins from human small intestinal and colonic tissues, determine their in vitro antimicrobial activity in order to relate structure and function, and use model systems of enteric defensin expression as tools to examine their expression in response to inflammatory stimuli. Epithelial defensin peptides are likely to equip mucosal surfaces with a previously unrecognized defensive capability that complements other well-defined antimicrobial defenses. Determining the strategies of defense that have evolved utilizing these antimicrobial peptides will enhance our understanding of basic host defense mechanisms and may lead to the development of useful therapeutics.
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