Maintenance of cellular homeostasis requires synthesis of new proteins and organelles and efficient removal of """"""""worn out"""""""" cell components. Degradation processes are carried via two mechanisms, the ubiquitin-proteasome pathway and the autophagy-lysosome pathway. Defects in both of these catabolic pathways have been linked to pathogenesis of a variety of diseases. Autophagic function declines with age leading to accumulation of cellular debris, injury and cell senescence or death. This observation leads to the central hypothesis of this application, that autophagic dysfunction contributes to the late onset and/or acute exacerbations typical of interstitial lung disease (ILD). We postulate that autophagic dysfunction in alveolar epithelial cells leads to chronic epithelial cell injury that, in turn, promotes aberrant fibrotic repair. Surfactant protein C (SP-C) represents a highly tractable model to study the role of autophagy in ILD: SP-C expression in the lung is limited to the type II epithelial cell and mutations in the gene encoding SP-C (SFTPC) are associated with sporadic and heritable ILD. In this application, we present preliminary findings that specific SFTPC mutations are degraded exclusively by autophagy and additional new data implicating autophagy in the pathogenesis of ILD.
Three specific aims are proposed to study SFTPC mutations in transfected cells, novel transgenic mouse models and lung tissue from human ILD patients, with the goal of identifying the molecular pathway(s) that targets mutant SP-C to autophagy and the role of this pathway in the pathogenesis of ILD.
Specific Aim 1 will test the hypothesis that aggregation-prone, mutant SP-C proteins are selectively degraded by autophagy and that inhibition of this pathway leads to accumulation of cytotoxic SP-C.
Specific Aim 2 will test the hypothesis that a novel quality control pathway in the endoplasmic reticulum mediates rapid identification and delivery of SP-C to the autophagic pathway.
Specific Aim 3 will test the hypothesis that autophagic dysfunction in novel transgenic mouse models leads to epithelial cell injury that, in turn, promotes the onset and/or exacerbation of ILD. These studies will provide new diagnostic tools, new therapeutic targets and appropriate animal models to facilitate identification of pathogenetic pathways and development of novel treatment paradigms for ILD.

Public Health Relevance

Idiopathic Pulmonary Fibrosis (IPF) is one of the more common forms of interstitial lung disease. There are no effective treatment options for this disease and the mean survival time is three years following diagnosis. The absence of appropriate animal models represents an enormous impediment to understanding the natural history of IPF, identification of useful biomarkers for detection of at-risk individuals and prediction of disease progression, and development of novel treatment strategies. The goals of this application are to generate novel mouse models to begin to directly address these critical knowledge gaps and identify the molecular mechanisms underlying pathogenesis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Eu, Jerry Pc
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Cincinnati Children's Hospital Medical Center
United States
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Whitsett, Jeffrey A; Wert, Susan E; Weaver, Timothy E (2015) Diseases of pulmonary surfactant homeostasis. Annu Rev Pathol 10:371-93
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
Fritz, Jill M; Weaver, Timothy E (2014) The BiP cochaperone ERdj4 is required for B cell development and function. PLoS One 9:e107473
Hahn, David R; Na, Cheng-Lun; Weaver, Timothy E (2014) Reserve autophagic capacity in alveolar epithelia provides a replicative niche for influenza A virus. Am J Respir Cell Mol Biol 51:400-12
Fritz, Jill M; Dong, Mei; Apsley, Karen S et al. (2014) Deficiency of the BiP cochaperone ERdj4 causes constitutive endoplasmic reticulum stress and metabolic defects. Mol Biol Cell 25:431-40
Blackwell, Timothy S; Tager, Andrew M; Borok, Zea et al. (2014) Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med 189:214-22
Stewart, Gareth A; Ridsdale, Ross; Martin, Emily P et al. (2012) 4-Phenylbutyric acid treatment rescues trafficking and processing of a mutant surfactant protein-C. Am J Respir Cell Mol Biol 47:324-31
Young, Lisa R; Gulleman, Peter M; Bridges, James P et al. (2012) The alveolar epithelium determines susceptibility to lung fibrosis in Hermansky-Pudlak syndrome. Am J Respir Crit Care Med 186:1014-24