PROJECT 3: The goal of this proposal is to discover genetic variants that are central to the development of idiopathic interstifial pneumonia (IIP), including the most common and severe form known as idiopathic pulmonary fibrosis (IPF). Evidence for a genefic basis of IIP is substanfial. Rare mutafions in genes that maintain telomere length (TERT and TERC) have been reported in familial interstifial pneumonia (FIP). Two families with FIP have been shown to have mutations in surfactant protein C. We have performed a limited linkage study in 82 families with FIP, and have identified linked regions on chromosomes 10, 11, and 12. Further, we have found common variants in MUC5AC (chrl 1 positional candidate) that are associated with both FIP and IPF. Approximately 40% of families with FIP have discordant types of IIP among family members, suggesfing that IIP may be caused by common gene variants that are altered phenotypically by environmental exposures. In fact, FIP and IPF can be influenced by environmental exposures, occurring more frequently in males (probably due to occupational exposures), and among cigarette smokers. Although controversial, an associafion of herpesvirus with IPF has been developed, most cleariy with Epstein Barr Virus (EBV);however, there is evidence that other viruses may be relevant. Thus, we hypothesize that combinations of genefic variations or polymorphisms interact with cigarette smoke and/or viruses to predispose individuals to the clinical development of pulmonary fibrosis.
Specific aims for this project are to: 1) perform a linkage study in affected individuals with familial IIP;2) determine the validity ofthe genes/loci identified in FIP by tesfing the significance of genefic variants within these genes and loci in subjects with sporadic IIP and controls;3) comprehensively assess the presence of viruses in lung fissue from study subjects with sporadic IIP and controls;and 4) identify gene-environment (cigarette smoking and viruses) interacfions in IIP. This project will be conducted in 3 separate stages with each stage focusing on an independent population of subjects with IIP. The overarching concept is that the inifial focus on FIP will identify genetic variants that result in relatively large effects that should be generalizable to sporadic IIP and will be even more pronounced when we narrow the biologicalphysiological phenotype by using environmental exposures. Using this approach, we will elucidate important genefic factors in IIP and determine how gene-environment interacfions impact pathogenesis.
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| Sivley, R Michael; Sheehan, Jonathan H; Kropski, Jonathan A et al. (2018) Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia. BMC Bioinformatics 19:18 |
| 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 |
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