# Mechanisms of DNA damage induced emphysema

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $627,061

## Abstract

Abstract
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

## Key facts

- **NIH application ID:** 10431937
- **Project number:** 5R01HL119476-07
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mary Y Armanios
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $627,061
- **Award type:** 5
- **Project period:** 2014-07-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10431937

## Citation

> US National Institutes of Health, RePORTER application 10431937, Mechanisms of DNA damage induced emphysema (5R01HL119476-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10431937. Licensed CC0.

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