Human surfactant protein B (SP-B) is synthesized as a preproprotein of 381 amino acids which 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-Bresults 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. Although the SP-B (-/-)phenotype has been well-characterized, the molecular mechanism(s) underlying SP-B action are completely unknown. This proposal will test the central hypothesis that the fusogenic and/or lytic properties of the 79 residue mature SP-Bpeptide are critical for the (1) processing,of SP-Cproprotein to its mature peptide, (2) organization of phospholipids in lamellar bodies, and (3) formation and maintenance of a surfactant film in the alveolus.
Specific aim 1 will test the hypothesis that the mature SP-B peptide is necessary and sufficient to correct phospholipid packaging in lamellar bodies and restore processing of the SP-C proprotein to its mature peptide in Type II cells of SP-B (-/-) mice.
Specific aim 2 will test the hypothesis that amphipathic helix 1 of the mature peptide is critical for the fusogenic activity of SP-B in vitro.
Specific aim 3 will test the hypothesis that inactivation of the fusogenic activity of SP-B in transgenic mice results in defects in lamellar body organization, SP-C processing and/or lung function.
| Whitsett, Jeffrey A; Weaver, Timothy E (2015) Alveolar development and disease. Am J Respir Cell Mol Biol 53:1-7 |
| Coya, Juan Manuel; Akinbi, Henry T; Sáenz, Alejandra et al. (2015) Natural Anti-Infective Pulmonary Proteins: In Vivo Cooperative Action of Surfactant Protein SP-A and the Lung Antimicrobial Peptide SP-BN. J Immunol 195:1628-36 |
| Ridsdale, Ross; Na, Cheng-Lun; Xu, Yan et al. (2011) Comparative proteomic analysis of lung lamellar bodies and lysosome-related organelles. PLoS One 6:e16482 |
| McDowell, Susan A; Ma, Yan; Kusano, Ryosuke et al. (2011) Simvastatin is protective during Staphylococcus aureus pneumonia. Curr Pharm Biotechnol 12:1455-62 |
| Yang, Li; Johansson, Jan; Ridsdale, Ross et al. (2010) Surfactant protein B propeptide contains a saposin-like protein domain with antimicrobial activity at low pH. J Immunol 184:975-83 |
| Perez-Gil, Jesus; Weaver, Timothy E (2010) Pulmonary surfactant pathophysiology: current models and open questions. Physiology (Bethesda) 25:132-41 |
| Ikegami, Machiko; Weaver, Timothy E; Grant, Shawn N et al. (2009) Pulmonary surfactant surface tension influences alveolar capillary shape and oxygenation. Am J Respir Cell Mol Biol 41:433-9 |
| Bein, Kiflai; Wesselkamper, Scott C; Liu, Xiangdong et al. (2009) Surfactant-associated protein B is critical to survival in nickel-induced injury in mice. Am J Respir Cell Mol Biol 41:226-36 |
| Ryan, Marnie A; Akinbi, Henry T; Serrano, Alicia G et al. (2006) Antimicrobial activity of native and synthetic surfactant protein B peptides. J Immunol 176:416-25 |
| Akei, Hiroko; Whitsett, Jeffrey A; Buroker, Michelle et al. (2006) Surface tension influences cell shape and phagocytosis in alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 291:L572-9 |
Showing the most recent 10 out of 29 publications
