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
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.
| Burman, Ankita; Kropski, Jonathan A; Calvi, Carla L et al. (2018) Localized hypoxia links ER stress to lung fibrosis through induction of C/EBP homologous protein. JCI Insight 3: |
| Wilfong, Erin M; Lentz, Robert J; Guttentag, Adam et al. (2018) Interstitial Pneumonia With Autoimmune Features: An Emerging Challenge at the Intersection of Rheumatology and Pulmonology. Arthritis Rheumatol 70:1901-1913 |
| Celada, Lindsay J; Kropski, Jonathan A; Herazo-Maya, Jose D et al. (2018) PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-?1 production. Sci Transl Med 10: |
| Hewlett, Justin C; Kropski, Jonathan A; Blackwell, Timothy S (2018) Idiopathic pulmonary fibrosis: Epithelial-mesenchymal interactions and emerging therapeutic targets. Matrix Biol 71-72:112-127 |
| Kropski, Jonathan A; Blackwell, Timothy S (2018) Endoplasmic reticulum stress in the pathogenesis of fibrotic disease. J Clin Invest 128:64-73 |
| Evans, Christopher M; Dickey, Burton F; Schwartz, David A (2018) E-Cigarettes: Mucus Measurements Make Marks. Am J Respir Crit Care Med 197:420-422 |
| Lentz, Robert J; Taylor, Trevor M; Kropski, Jonathan A et al. (2018) Utility of Flexible Bronchoscopic Cryobiopsy for Diagnosis of Diffuse Parenchymal Lung Diseases. J Bronchology Interv Pulmonol 25:88-96 |
| Brittain, Evan L; Thennapan, Thennapan; Maron, Bradley A et al. (2018) Update in Pulmonary Vascular Disease 2016 and 2017. Am J Respir Crit Care Med 198:13-23 |
| Kook, Seunghyi; Qi, Aidong; Wang, Ping et al. (2018) Gene-edited MLE-15 Cells as a Model for the Hermansky-Pudlak Syndromes. Am J Respir Cell Mol Biol 58:566-574 |
| Juge, Pierre-Antoine; Lee, Joyce S; Ebstein, Esther et al. (2018) MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease. N Engl J Med 379:2209-2219 |
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