Pulmonary fibrosis characterizes a heterogeneous group of lung disorders with irreversible destruction of lung architecture and disruption of gas exchange. The prototype of these diseases, idiopathic pulmonary fibrosis (IPF), has a short median life expectancy from diagnosis to death. Mutations in the genes encoding the protein component (TERT) or RNA component (TERC) of telomerase, a ribonucleoprotein enzyme that catalyzes the addition of hexameric nucleotide repeats to the ends of linear chromosomes, cause disease in a subset of kindreds with familial pulmonary fibrosis. An equal number of families has evidence of telomerase dysfunction, with very short peripheral blood telomere lengths, but no coding mutations in the telomerase genes. Our hypothesis is that short telomere lengths, caused by mutations in genes other than TERT or TERC, represent an important mechanism underlying IPF. In this grant application we merge traditional clinical phenotyping and linkage methods with next generation exome sequencing to provide new insights into IPF genetics. First, we will characterize the clinical phenotype associated with very short telomere lengths in rare kindreds that demonstrate autosomal dominant co-segregation of pulmonary fibrosis and short telomere lengths. Since extreme phenotypes represent a powerful tool for gene discovery, we will use clinical evaluations and analyses of tissue telomerase expression, lung transcriptome signatures and circulating biomarkers to characterize the short telomere IPF phenotype. Second, we will use next generation exome sequencing to identify rare candidate variants in the discovery cohort of kindreds without mutations in known familial pulmonary fibrosis genes. The datasets will be filtered and prioritized by four independent methods: (1) by genomic regions co- segregating with the phenotypes of lung fibrosis and/or short telomere length, (2) by allele frequency, (3) by predicted deleterious effects on protein function and (4) b gene-based frequencies and their biological roles in telomere and fibrosis pathways.
The final aim will validate candidate variants by co-segregation in the kindreds they were discovered, by association studies and by investigations of protein variant function. These studies have the potential to break new grounds by determining how telomere shortening leads to lung fibrosis. Our multi-pronged approach offers the promise of new targets for therapeutic intervention and will lead to better understanding of the pathogenesis of progressive lung fibrosis due to telomerase dysfunction.

Public Health Relevance

Idiopathic pulmonary fibrosis (IPF), a human disease of irreversible and progressive lung scarring, can be caused by mutations in the genes encoding telomerase. However, only half of the kindreds with familial pulmonary fibrosis and short telomere lengths have telomerase mutations, suggesting that there are additional undiscovered genetic mechanisms of telomere shortening that lead to lung disease. This grant application focuses on identifying novel genetic mechanisms of lung fibrosis that are relevant to human aging.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL093096-10
Application #
9852179
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Vuga, Louis J
Project Start
2009-04-01
Project End
2020-04-30
Budget Start
2019-04-19
Budget End
2020-04-30
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Garcia, Christine Kim (2017) Whole-Exome Sequencing Insights into Adult Pulmonary Fibrosis. Repeating the Telomere Theme. Am J Respir Crit Care Med 196:7-9
Ley, Brett; Newton, Chad A; Arnould, Isabel et al. (2017) The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study. Lancet Respir Med 5:639-647
Maryoung, Lindley; Yue, Yangbo; Young, Ashley et al. (2017) Somatic mutations in telomerase promoter counterbalance germline loss-of-function mutations. J Clin Invest 127:982-986
Newton, Chad A; Kozlitina, Julia; Lines, Jefferson R et al. (2017) Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post-lung transplantation survival. J Heart Lung Transplant 36:845-853
Newton, Chad A; Batra, Kiran; Torrealba, Jose et al. (2017) Pleuroparenchymal fibroelastosis associated with telomerase reverse transcriptase mutations. Eur Respir J 49:
Mathai, Susan K; Newton, Chad A; Schwartz, David A et al. (2016) Pulmonary fibrosis in the era of stratified medicine. Thorax 71:1154-1160
Newton, Chad A; Batra, Kiran; Torrealba, Jose et al. (2016) Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive. Eur Respir J 48:1710-1720
Xing, Chao; Garcia, Christine Kim (2016) Epigenetic inheritance of telomere length obscures identification of causative PARN locus. J Med Genet 53:356-8
Garcia, Christine Kim (2015) Running short on time: lung transplant evaluation for telomere-related pulmonary fibrosis. Chest 147:1450-1452

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