PROJECT 2: Idiopathic Pulmonary Fibrosis (IPF) is a destructive lung disease of unknown cause that has no proven therapy. IPF is associated with alveolar epithelial cell abnormalities, progressive lung scarring, and inflammation, resulting in respiratory failure and death. Studies involving individuals with the familial form of IPF, familial interstitial pneumonia (FIP), have aided understanding of genetic variations associated with progressive pulmonary fibrosis. We have previously reported two rare variants (RVs) in the Surfactant Protein C (SFTPC) gene associated with FIP. Both SFTPC RVs were found to produce altered Surfactant C proteins that were toxic to type II alveolar epithelial cells. We have also identified RVs in Telomerase genes (TERT &TERC) associated with loss of telomerase activity that cause FIP. In this project, we will investigate the hypothesis that development of IPF is influenced by multiple genetic factors that variably contribute to disease predisposition, depending on whether the variation is a rare variant (RV) of major effect or a common variant (CV) of minor effect. In combination with appropriate environmental or cellular triggers, individuals who possess these RVs and CVs may develop IPF (or FIP). In this project, we will focus on discovering and characterizing RVs of major effect that co-segregate with FIP to determine how and why they cause FIP. Identification of RVs associated with FIP will guide us towards molecular pathways that are relevant to the pathogenesis of IPF. We will utilize a combination of approaches to identify and characterize the effects of RVs in various candidate pathways in the following specific aims: 1) Characterize sequence variations in genes of the Telomerase and Surfactant Pathways as well as other select candidate genes for FIP, 2) Determine the contribution and effects of Telomerase Pathway defects to FIP, 3) Determine the contribution and effects of variations in the Surfactant Pathway and other candidate genes to FIP. Using this approach, we will elucidate genetic, cellular, and molecular pathways that are important in FIP pathogenesis

Public Health Relevance

Interstitial lung diseases, including the idiopathic interstitial pneumonias, are a substantial 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 #
5P01HL092870-03
Application #
8374687
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$406,134
Indirect Cost
$145,792
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Molyneaux, Philip L; Willis-Owen, Saffron A G; Cox, Michael J et al. (2017) Host-Microbial Interactions in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 195:1640-1650
Kropski, Jonathan A; Young, Lisa R; Blackwell, Timothy S et al. (2017) Reply: The Genetic Diagnosis of Interstitial Lung Disease: A Need for an International Consensus. Am J Respir Crit Care Med 195:1539-1540
Kropski, Jonathan A; Reiss, Sara; Markin, Cheryl et al. (2017) Rare Genetic Variants in PARN Are Associated with Pulmonary Fibrosis in Families. Am J Respir Crit Care Med 196:1481-1484
Kropski, Jonathan A; Young, Lisa R; Cogan, Joy D et al. (2017) Genetic Evaluation and Testing of Patients and Families with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 195:1423-1428
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Allen, Richard J; Porte, Joanne; Braybrooke, Rebecca et al. (2017) Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study. Lancet Respir Med 5:869-880
Lentz, Robert J; Taylor, Trevor M; Kropski, Jonathan A et al. (2017) Utility of Flexible Bronchoscopic Cryobiopsy for Diagnosis of Diffuse Parenchymal Lung Diseases. J Bronchology Interv Pulmonol :
Mathai, Susan K; Newton, Chad A; Schwartz, David A et al. (2016) Pulmonary fibrosis in the era of stratified medicine. Thorax 71:1154-1160
Nevel, Rebekah J; Garnett, Errine T; Worrell, John A et al. (2016) Persistent Lung Disease in Adults with NKX2.1 Mutation and Familial Neuroendocrine Cell Hyperplasia of Infancy. Ann Am Thorac Soc 13:1299-304

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