PROJECT 3: The goal of this proposal is to discover genetic variants that are central to the development of idiopathic interstitial pneumonia (IIP), including the most common and severe form known as idiopathic pulmonary fibrosis (IPF). Evidence for a genetic basis of IIP is substantial. Rare mutations in genes that maintain telomere length (TERT and TERC) have been reported in familial interstitial 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 (chr11 positional candidate) that are associated with both FIP and IPF. Approximately 40% of families with FIP have discordant types of IIP among family members, suggesting 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 association of herpesvirus with IPF has been developed, most clearly with Epstein Barr Virus (EBV);however, there is evidence that other viruses may be relevant. Thus, we hypothesize that combinations of genetic 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 of the genes/loci identified in FIP by testing the significance of genetic variants within these genes and loci in subjects with sporadic IIP and controls;3) comprehensively assess the presence of viruses in lung tissue from study subjects with sporadic IIP and controls;and 4) identify gene-environment (cigarette smoking and viruses) interactions 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 initial 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 biological-physiological phenotype by using environmental exposures. Using this approach, we will elucidate important genetic factors in IIP and determine how gene-environment interactions impact 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.
|Mathai, Susan K; Schwartz, David A; Warg, Laura A (2014) Genetic susceptibility and pulmonary fibrosis. Curr Opin Pulm Med 20:429-35|
|Molyneaux, Phillip L; Cox, Michael J; Willis-Owen, Saffron A G et al. (2014) The role of bacteria in the pathogenesis and progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 190:906-13|
|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|
Showing the most recent 10 out of 24 publications