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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Vanderbilt University Medical Center
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Young, Lisa R; Gulleman, Peter M; Short, Chelsi W et al. (2016) Epithelial-macrophage interactions determine pulmonary fibrosis susceptibility in Hermansky-Pudlak syndrome. JCI Insight 1:e88947
Benjamin, John T; van der Meer, Riet; Im, Amanda M et al. (2016) Epithelial-Derived Inflammation Disrupts Elastin Assembly and Alters Saccular Stage Lung Development. Am J Pathol 186:1786-800
Saxon, Jamie A; Cheng, Dong-Sheng; Han, Wei et al. (2016) p52 Overexpression Increases Epithelial Apoptosis, Enhances Lung Injury, and Reduces Survival after Lipopolysaccharide Treatment. J Immunol 196:1891-9
Fingerlin, Tasha E; Zhang, Weiming; Yang, Ivana V et al. (2016) Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia. BMC Genet 17:74
Nakano, Yasushi; Yang, Ivana V; Walts, Avram D et al. (2016) MUC5B Promoter Variant rs35705950 Affects MUC5B Expression in the Distal Airways in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:464-6
Claar, Dru D; Larkin, Emma K; Bastarache, Lisa et al. (2016) A Phenome-Wide Association Study Identifies a Novel Asthma Risk Locus Near TERC. Am J Respir Crit Care Med 193:98-100
Mathai, Susan K; Pedersen, Brent S; Smith, Keith et al. (2016) Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:1151-60
Kropski, Jonathan A; Young, Lisa R; Cogan, Joy D et al. (2016) Genetic Evaluation and Testing of Patients and Families with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med :
Richmond, Bradley W; Brucker, Robert M; Han, Wei et al. (2016) Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency. Nat Commun 7:11240
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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