Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) with no effective treatment options and a mean survival of 3 years after diagnosis. The natural history of the disease is poorly understood because of the lack of an appropriate animal model. Familial forms of the disease account for less than 5% of total IPF cases and are characterized by autosomal dominant inheritance with variable penetrance related to the influence of both genetic modifiers and environmental factors. Mutations in the gene (SFTPC) encoding surfactant protein C (SP-C?exon4 and SP-CL188Q) provide an unique opportunity to identify molecular pathways underlying familial ILD. Our preliminary studies in cell culture have identified unique molecular complexes involved in the detection and rapid degradation of mutant SP-C;further, we have shown that cells expressing mutant SP-C and infected with respiratory syncticial virus accumulate misfolded SP-C and are much more susceptible to viral-induced cell death than cells expressing the wild type protein. These key in vitro findings lead to the central hypothesis that environmental stress superimposed on a SFTPC mutation leads to accumulation of misfolded, cytotoxic SP-C that, in turn, results in type II epithelial cell injury/death, which is the inciting event in SFTPC-associated familial ILD.
Three specific aims are proposed to test this hypothesis:
Specific aim 1 will test the hypothesis that ERAD (a cytoprotective pathway) rapidly identifies and degrades mutant SP-C preventing intracellular accumulation, type II epithelial cell apoptosis, and progression to ILD.
Specific aim 2 will test the hypothesis that viral infection superimposed on an Sftpc mutation leads to accumulation of cytotoxic SP-C and type II epithelial cell apoptosis that, in turn, triggers the onset of ILD or accelerates pathogenesis.
Specific aim 3 will test the hypothesis that inhibiting accumulation of mutant SP-C in vivo will prevent progression to ILD. Studies proposed in this application will generate the first mouse model of familial IPF and determine if an environmental insult is absolutely required for onset of the disease;further, this model will permit testing of the biologic relevance of findings from in vitro studies, in particular the hypothesis that accumulation of cytotoxic SP-C drives progression to ILD. The mouse model will also facilitate translational studies with the long-term goals of (1) testing the feasibility of reversing the fibrogenic process by transplantation of adult progenitor cells, (2) identifying new drugs that enhance clearance of mutant SP-C (and, potentially, other disease-causing mutant proteins) and prevent ILD in affected mice, and (3) identifying candidate genes for early detection of disease in asymptomatic patients. Thus, the overall, long term-goal of this proposal is to identify novel diagnostic and treatment strategies for a disease in which the current standard of care is palliative.

Public Health Relevance

The association between mutations in the SFTPC locus and familial IPF represents a truly unique opportunity to generate an animal model for a lethal disease with an uncharacterized natural history. Although SFTPC- associated IPF is a very rare disease subset, it is likely that the molecular pathways leading to epithelial cell apoptosis may be shared with other familial forms of the disease (e.g. mutations in TERT or TR) and pathways downstream of apoptosis may well be informative for non-familial, idiopathic IPF. For this reason, we have proposed a broad range of studies centered around an Sftpc mutant mouse model that will facilitate development/identification of novel disease biomarkers, drugs/drug targets, and therapies.

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
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