Surfactant protein C (SP-C) is exclusively synthesized by pulmonary type II epithelial cells which process the proprotein to the hydrophobic mature peptide for secretion into the alveolar airspace. Mutations in the SP-C gene were recently linked to familial and sporadic interstitial lung disease. The results of our preliminary studies indicate that expression of a disease-associated SP-C mutation in type II epithelial cells of transgenic mice leads to epithelial cell death and profoundly perturbed lung morphogenesis strongly suggesting that mutations in the SP-C gene can cause lung disease. The central hypothesis of this application is that mutations in the SP-C gene result in misfolding of the proprotein and saturation of the ERAD pathway leading to accumulation of a cytotoxic form of the protein.
Four specific aims are proposed to test the following hypotheses: (1) The inability to rapidly degrade mutant proSP-C via ERAD results in accumulation of a cytotoxic form of the proprotein; (2) Novel ERAD proteins are involved in the detection and/or degradation of mutant proSP-C; (3) A quality control receptor specifically detects mutant proSP-C and sorts the proprotein for degradation via the ubiquitin-proteasome pathway; and (4) Augmentation of ERAD in vivo will accelerate degradation of mutant proSP-C, thereby preventing/reducing mutant proSP-C induced lung dysmorphogenesis. The long term goal of this work is to identify proteins that selectively enhance ERAD for use as potential therapeutic targets in diseases associated with protein misfolding.
| Whitsett, Jeffrey A; Weaver, Timothy E (2015) Alveolar development and disease. Am J Respir Cell Mol Biol 53:1-7 |
| Conkright, Juliana J; Apsley, Karen S; Martin, Emily P et al. (2010) Nedd4-2-mediated ubiquitination facilitates processing of surfactant protein-C. Am J Respir Cell Mol Biol 42:181-9 |
| Xu, Yan; Zhang, Minlu; Wang, Yanhua et al. (2010) A systems approach to mapping transcriptional networks controlling surfactant homeostasis. BMC Genomics 11:451 |
| Suzuki, Takuji; Sakagami, Takuro; Young, Lisa R et al. (2010) Hereditary pulmonary alveolar proteinosis: pathogenesis, presentation, diagnosis, and therapy. Am J Respir Crit Care Med 182:1292-304 |
| Hardie, William D; Hagood, James S; Dave, Vrushank et al. (2010) Signaling pathways in the epithelial origins of pulmonary fibrosis. Cell Cycle 9:2769-76 |
| Whitsett, Jeffrey A; Wert, Susan E; Weaver, Timothy E (2010) Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease. Annu Rev Med 61:105-19 |
| Kramer, Elizabeth L; Mushaben, Elizabeth M; Pastura, Patricia A et al. (2009) Early growth response-1 suppresses epidermal growth factor receptor-mediated airway hyperresponsiveness and lung remodeling in mice. Am J Respir Cell Mol Biol 41:415-25 |
| Wang, Mei; Bridges, James P; Na, Cheng-Lun et al. (2009) Meckel-Gruber syndrome protein MKS3 is required for endoplasmic reticulum-associated degradation of surfactant protein C. J Biol Chem 284:33377-83 |
| Hardie, William D; Glasser, Stephan W; Hagood, James S (2009) Emerging concepts in the pathogenesis of lung fibrosis. Am J Pathol 175:3-16 |
| Korfhagen, Thomas R; Le Cras, Timothy D; Davidson, Cynthia R et al. (2009) Rapamycin prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 41:562-72 |
Showing the most recent 10 out of 91 publications
