Pulmonary fibrosis characterizes a heterogeneous group of incurable lung disorders with progressive, irreversible destruction of the lung architecture and disruption of gas exchange. The prototype of these diseases, idiopathic pulmonary fibrosis (IPF), has a median life expectancy of three years from diagnosis to death. Currently, no effective treatment is available for this disease. The first clue as to the molecular mechanism responsible for IPF emerged from the discovery by two groups, including our group, that a subset of pulmonary fibrosis is caused by mutations in the genes encoding the protein component (TERT) and the RNA component (TERC) of telomerase, a ribonucleoprotein enzyme that catalyzes the addition of hexameric nucleotide repeats to the ends of linear chromosomes. In our studies, all affected members with mutations in telomerase have evidence of shortened telomere lengths in circulating leukocytes. However, mutations in these genes comprise less than 15% of patients with the familial form of the disease and less than 3% of patients with the more common sporadic form of the disease. Here we will characterize the genetic etiology of pulmonary fibrosis in a large collection of familial and sporadic pulmonary fibrosis subjects. First, we will determine if telomere dysfunction and telomere shortening is a more generalized feature of familial and sporadic pulmonary fibrosis in subjects who do not have telomerase mutations, as our preliminary studies suggest. Second, we will determine if mutations in other genes involved in telomere maintenance contribute to PF in the subset of patients without coding mutations in telomerase. Third, we will map new genetic loci that cause pulmonary fibrosis in large kindreds where the disease fails to co-segregate with the genes known to cause lung scarring. These studies have the potential for breaking new conceptual grounds for determining the underlying molecular pathogenesis of pulmonary fibrosis. Our multi-pronged approaches offer the promise of providing new targets for therapeutic intervention for this lethal, age-associated lung disease.

Public Health Relevance

Idiopathic pulmonary fibrosis (IPF) is the prototype of a group of lethal diseases characterized by progressive, irreversible, lung scarring. A recent clue as to the genetic underpinnings of this disorder came from our finding that mutations in the genes encoding telomerase cause the disease in a subset of families with autosomal dominant pulmonary fibrosis. In this grant we will investigate the link between telomerase dysfunction and pulmonary fibrosis through an integrated, clinical and genetic approach to patients and their families with this devastating disorder.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Eu, Jerry Pc
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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Garcia, Christine Kim (2018) Insights from human genetic studies of lung and organ fibrosis. J Clin Invest 128:36-44
Newton, Chad A; Batra, Kiran; Torrealba, Jose et al. (2017) Pleuroparenchymal fibroelastosis associated with telomerase reverse transcriptase mutations. Eur Respir J 49:
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
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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