EXCEED THE SPACE PROVIDED. Human surfactant protein B (SP-B) is synthesized as a preproprotein of 381 amino acids that is processed to the 79 residue mature peptide by proteolytic cleavage of N- and C-terminal propeptides in the biosynthetic pathway of the alveolar type II epithelial cell. SP-B is the only surfactant-associated protein which is absolutely required for postnatal lung function and survival. Complete deficiency of SP-B results in lethal, neonatal respiratory distress syndrome and is characterized by a virtual absence of lung compliance, highly disorganized lamellar bodies and greatly diminished levels of SP-C mature peptide. The results of preliminary studies indicate that SP-B-derived peptides also exhibit potent bactericidal activity. The current and proposed studies will test the central hypothesis that SP-B plays a central role in maintaining both alveolar structure and sterility. Studies are proposed to identify the antimicrobial domains in the N-terminal propeptide (residues 24-199), mature peptide (residues 200-279), and C-terminal peptide (residues 280-387) using synthetic peptide analogues. The antimicrobial spectrum, selectivity for prokaryotic membranes and mechanism(s) of pathogen killing will be evaluated for each of the three antimicrobial peptide domains. Individual and concatamerized forms of the peptides will be expressed in transgenic mice to determine if broad spectrum resistance to airway infections is conferred by SP-B derived peptides. The proposed studies represent an integrated approach to identify novel antimicrobial peptides derived from SP-B. These peptides may be important adjuncts or, in the case of antibiotic resistant organisms, replacements for conventional antibiotic therapies.
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| Whitsett, Jeffrey A; Weaver, Timothy E (2015) Alveolar development and disease. Am J Respir Cell Mol Biol 53:1-7 |
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