PROJECT 1: The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains poorly defined;however, identificafion of mutafions in the gene encoding surfactant protein C (SP-C) in the familial form of IPF (FIP), along with several other lines of evidence, suggests that alveolar epithelial cells (AECs) play a key role in disease progression. Our data indicate that abnormal processing of pro-SP-C by AECs leads to endoplasmic reficulum (ER) stress, acfivafion ofthe unfolded protein response, and cell death. We also show that ER stress occurs frequently in AECs in IPF, suggesfing that this pathway contributes to disease. In addifion, we show that herpesviruses are commonly localized to AECs in IPF and could contribute to ER stress and AEC injury. Finally, we have identified loss-of-funcfion mutations in telomerase genes that segregate with disease in some FIP families, suggesting that defective telomerase leads to telomere shortening and apoptosis of type II AECs. Identificafion of individuals in FIP families with early fibrotic changes will provide a valuable resource for invesfigafions aimed at defining primary disease mechanisms. In this study, we will ufilize CT scanning to identify asymptomafic individuals at risk for FIP who have radiographic changes consistent with early fibrosis. Subjects with eariy FIP and controls will undergo bronchoscopy for sample collecfion to test the following hypothesis. Genefic or acquired factors that increase the suscepfibility of lung epithelial cells to injury and/or apoptosis underiie the pathogenesis of IPF. Exposure of vulnerable epithelial cells to common injurious/toxic environmental sfimuli results in extensive injury with limited capacity for alveolar repair, leading to fibrofic remodeling. The following specific aims will invesfigate the role of AECs in early FIP: 1) to evaluate epithelial cell injury/apoptosis, markers of ER stress, and surfactant protein producfion in the lungs of pafients with eariy FIP, 2) to invesfigate whether herpesvirus infection occurs in eariy FIP, contributes to ER stress, and is associated with alveolar epithelial cell injury and, 3) to determine whether differenfial telomere length occurs in epithelial cells from patients with eariy FIP and correlates with epithelial cell injury. By elucidafing crifical components of eariy stage disease, our study will define novel therapeufic targets.

Public Health Relevance

Interstitial lung diseases, including the idiopathic interstitial pneumonias, are a substanfial cause of morbidity and mortality for which there are no effective treatments. In this program, we will study the genetics and underlying biological mechanisms that lead to progressive fibrosis in the lungs. Our integrated approach will lead to new concepts in disease pathogenesis and identification of novel treatment strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL092870-05
Application #
8598496
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$529,608
Indirect Cost
$175,404
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Shi, Chanjuan; Washington, M Kay; Chaturvedi, Rupesh et al. (2014) Fibrogenesis in pancreatic cancer is a dynamic process regulated by macrophage-stellate cell interaction. Lab Invest 94:409-21
Kropski, Jonathan A; Mitchell, Daphne B; Markin, Cheryl et al. (2014) A novel dyskerin (DKC1) mutation is associated with familial interstitial pneumonia. Chest 146:e1-7
Kropski, Jonathan A; Lawson, William E; Young, Lisa R et al. (2013) Genetic studies provide clues on the pathogenesis of idiopathic pulmonary fibrosis. Dis Model Mech 6:9-17
Atochina-Vasserman, Elena N; Biktasova, Asel; Abramova, Elena et al. (2013) Aquaporin 11 insufficiency modulates kidney susceptibility to oxidative stress. Am J Physiol Renal Physiol 304:F1295-307
Peljto, Anna L; Zhang, Yingze; Fingerlin, Tasha E et al. (2013) Association between the MUC5B promoter polymorphism and survival in patients with idiopathic pulmonary fibrosis. JAMA 309:2232-9
Hunninghake, Gary M; Hatabu, Hiroto; Okajima, Yuka et al. (2013) MUC5B promoter polymorphism and interstitial lung abnormalities. N Engl J Med 368:2192-200
Lawson, William E; Blackwell, Timothy S (2013) ýý-Catenin and CCNs in lung epithelial repair. Am J Physiol Lung Cell Mol Physiol 304:L579-81
Seibold, Max A; Smith, Russell W; Urbanek, Cydney et al. (2013) The idiopathic pulmonary fibrosis honeycomb cyst contains a mucocilary pseudostratified epithelium. PLoS One 8:e58658

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