# Mechanisms of Telomere-Mediated Lung Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $384,352

## Abstract

Abstract
Age associated lung diseases, including chronic obstructive pulmonary disease (COPD) and idiopathic
pulmonary fibrosis (IPF), are devastating diseases that limit respiratory capacity and are responsible for an
enormous burden on our country’s health care system. There are essentially no treatments for these diseases
except for lung transplantation. Advanced age is a significant risk factors for COPD and PF yet how it
contributes to disease pathogenesis is not known. Recently, mutations in the genes responsible for telomere
maintenance have been recognized as the most common identifiable cause of IPF and a significant fraction
COPD. This discovery provides a new framework for understanding lung disease and may provide a link to
aging.
 Telomeres are DNA-protein caps on the ends of each of chromosomes that function as biologic clocks.
Telomeres shorten with age and when they become too short, they trigger cellular senescence (permanent cell
cycle arrest) or death. Unexpectedly, the lung is the organ most frequently affected by short telomeres and the
mechanisms that lead to lung disease are not known. We have developed a novel mouse model that permits
induction of telomere dysfunction in specific cell-types within the lung. When triggered, telomere failure leads to
senescence, rather than apoptosis, in lung epithelial cells. Because the fraction of senescent cells increases as
we age, this model provides an opportunity to examine the consequences of aging in specific cells and tissues.
 This proposal aims to explore the mechanisms by which telomeres dysfunction and subsequent cellular
senescence cause lung disease. We will dissect the consequences of cellular senescence in three related
aims. In each aim, we examine different aspects of cellular senescence on lung biology. In Aim 1, we will
investigate the consequences of inhibited cell proliferation on lung epithelial cells and examine if they can
contribute to lung regeneration after pneumonectomy. In Aim 2, we will characterize proteins that are secreted
by senescent epithelial cells and determine their role in chronic inflammation. We will also test if they are
present in clinical IPF samples. Finally, in Aim 3, we will determine if telomere dysfunction and senescence are
sufficient to cause mitochondrial dysfunction in the lung epithelium. We hope that these data will not only
contribute to our understanding of lung disease, but also suggest novel approaches to treating it.

## Key facts

- **NIH application ID:** 10445011
- **Project number:** 5R01HL135062-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jonathan K. Alder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $384,352
- **Award type:** 5
- **Project period:** 2018-07-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445011

## Citation

> US National Institutes of Health, RePORTER application 10445011, Mechanisms of Telomere-Mediated Lung Disease (5R01HL135062-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10445011. Licensed CC0.

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