Pulmonary infections are responsible for significant morbidity and mortality, particularly in hosts with compromised defenses. One of the many important physiological roles of the epithelial cells of the respiratory mucosa is to provide defense of the mammalian airway from potential pathogenic agents present in inspired air. A more complete definition of the defense mechanisms of these cells will contribute to our understanding of the pathophysiology of airway disease, ultimately leading to more rational therapeutic interventions. The isolation and characterization of antimicrobial peptides, such as cecropins, magainins and defensins, in a variety of species and tissues has unveiled a previously unrecognized component of host defense. Recently, a novel, cysteine-rich antimicrobial peptide has been isolated and characterized from bovine tracheal mucosa, and its cDNA has been cloned. This peptide, named Trachea] Antimicrobial Peptide (TAP), is present in high abundance in the tracheal mucosa and has potent broad-spectrum antimicrobial activity in vitro. Preliminary data suggest that cells of the respiratory epithelium make this molecule. The goal of this project is to extend our understanding of biochemistry of this novel peptide. Several hypotheses are proposed: First, TAP expression is developmentally regulated and is made by epithelial cells of the trachea (and possibly by similar cells in other anatomical locations). Second, TAP is stored in airway epithelial cells. Third, a homologous peptide is made by human tracheal mucosal cells. Fourth, the structure and function of TAP is critically dependent on a defined cysteine pairing. To address these hypotheses the following experiments will be performed: 1. Tissue and developmental expression of TAP will be determined by messenger RNA analysis, including in situ hybridization; 2. Cellular and subcellular localization will be determined by immunohistochemistry; 3. The cDNA for human TAP will be cloned; 4. The disulfide-array for TAP will be determined. TAP is likely to contribute to the antimicrobial defense of the respiratory epithelium of mammals. The understanding of its biological role may lead to the eventual therapeutic modulation of endogenous antimicrobial peptide expression and may facilitate the development of therapeutic antimicrobials designed to work in the respiratory tract.
| Bevins, C L (1994) Antimicrobial peptides as agents of mucosal immunity. Ciba Found Symp 186:250-60;discussion 261-9 |
| Diamond, G; Jones, D E; Bevins, C L (1993) Airway epithelial cells are the site of expression of a mammalian antimicrobial peptide gene. Proc Natl Acad Sci U S A 90:4596-600 |
