This renewal application aims to understand the genetic determinants of emphysema susceptibility. Emphysema-chronic obstructive disease (COPD) affect at least 10 million individuals in the United States and are a major cause of mortality and disability around the world. Among smokers, only 10-15% COPD and genetic factors are known to contribute to this susceptibility. In the prior funding period, we identified mutant telomerase genes as a second Mendelian cause of familial and early-onset emphysema beyond alpha-1 antitrypsin deficiency. We documented a specific predilection in female smokers who comprised 90% of mutant telomerase-associated emphysema. In animal models, we identified alveolar stem cell senescence as a driver of alveolar destruction and inflammation. For this renewal application, we focus on understanding how genetic defects in DNA damage, beyond telomere dysfunction, contribute to emphysema biology and susceptibility. We have identified a new animal model in which females exposed to genotoxic damage develop lung disease but not males. For the proposed experiments, we will prospectively examine male-female differences in cigarette smoke susceptibility and define the contribution of defective DNA repair as a risk factor for human emphysema. The focus on sex differences in our proposal is particularly timely since there is evidence that elsewhere, and this phenomenon is expected to grow since cigarette smoke rates remain on the rise in women. The proposed therefore have the potential to fill gaps in understanding emphysema biology and susceptibility and to shed light on sex-specific differences of emphysema penetrance in a context of significant

Public Health Relevance

Emphysema is a leading cause of mortality and disability in the United States; it affects at least 3 million individuals in the United States and its burden especially in females continues to increase. This application examines how genetic factors accelerate lung damage in cigarette smoke-induced emphysema. The knowledge gained has the potential to inform public policies and platforms for preventing and reversing emphysema.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Postow, Lisa
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Cárdenes, Nayra; Álvarez, Diana; Sellarés, Jacobo et al. (2018) Senescence of bone marrow-derived mesenchymal stem cells from patients with idiopathic pulmonary fibrosis. Stem Cell Res Ther 9:257
Alder, Jonathan K; Hanumanthu, Vidya Sagar; Strong, Margaret A et al. (2018) Diagnostic utility of telomere length testing in a hospital-based setting. Proc Natl Acad Sci U S A 115:E2358-E2365
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Stanley, Susan E; Armanios, Mary (2015) The short and long telomere syndromes: paired paradigms for molecular medicine. Curr Opin Genet Dev 33:1-9

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