Pulmonary surfactant protein B (SP-B) is a 79 amino acid peptide that is associated with surfactant phospholipids in the alveolar space. Mutations in the SP-B gene that result in complete absence of SP-B are fatal in the neonatal period. The pathology associated with SP-B deficiency suggests that SP-B plays a critical role in the synthesis, assembly and metabolism of surfactant. The overall goal of this proposal is to elucidate the role of SP-B in surfactant homeostasis by characterizing the pathophysiology associated with cell-specific expression of SP-B constructs in vivo. Human SP-B constructs, under control of lung cell- specific promoters, will be expressed in SP-B knockout mice to achieve expression of the human transgene in a null background. The effect of transgene expression on lung structure and function will be assessed by biochemical, morphological, and physiological analyses of the surfactant system in fetal and neonatal offspring.
The specific aims of this study are to use these mice to study: 1) the functional consequences of over- and underexpression of SP-B; 2) the function of SP-B in Type II and Clara cells; 3) the function of the propeptide domains of the SP-B proprotein; and, 3) the role of inter- and intra-disulfide linkages in SP-B function. These studies will allow characterization of the function of SP-B in the context of the whole animal, define its role in surfactant homeostasis, and facilitate the design of an appropriate therapy for SP-B deficiency.
| 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 |
| 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 |
| Bridges, James P; Weaver, Timothy E (2006) Use of transgenic mice to study lung morphogenesis and function. ILAR J 47:22-31 |
| Ikegami, Machiko; Whitsett, Jeffrey A; Martis, Prithy C et al. (2005) Reversibility of lung inflammation caused by SP-B deficiency. Am J Physiol Lung Cell Mol Physiol 289:L962-70 |
| Melton, Kristin R; Nesslein, Lori L; Ikegami, Machiko et al. (2003) SP-B deficiency causes respiratory failure in adult mice. Am J Physiol Lung Cell Mol Physiol 285:L543-9 |
Showing the most recent 10 out of 23 publications
