# Accelerated Aging as a Cause of Chronic Lung Allograft Dysfunction

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2020 · —

## Abstract

Lung transplantation is a lifesaving option for veterans with end-stage lung diseases, in particular idiopathic
pulmonary fibrosis (IPF). Veterans appear to be disproportionately affected by IPF, a disease that has been
described as early aging of the lung. IPF is usually fatal unless the lungs are replaced by transplant. Even
following lung transplantation median survival is less than six years, limited primarily by chronic lung allograft
dysfunction (CLAD). Emerging data suggest that telomeres, the nucleoprotein caps that protect chromosomes
during cellular replication, are involved in IPF, but it is unknown whether telomeres also play a role in CLAD.
Were that to be the case, the same pathophysiology that necessitated transplant might also underlie its failure.
Our own preliminary data show that impaired telomeres in peripheral blood of lung allograft donors are linked
to decreased survival in lung allograft recipients. We also have found that telomere dysfunction in airway stem
cells is sufficient to induce the pathologic hallmarks of CLAD in an experimental murine model. In humans,
airway progenitor cells proliferate and differentiate to restore airway epithelial integrity following injury. Thus,
telomere dysfunction could lead to airway epithelial cell progenitor failure, resulting in denuded airways that
are subsequently replaced by fibrotic tissue. With the support of this Merit Award, we will test the innovative
hypothesis that telomere dysfunction leads to CLAD. In Study Aim 1, we will evaluate the associations
between telomere genetic variants and CLAD in a large established multi-center cohort of lung transplant
recipients. Common genetic variants resulting in short telomeres will be sequenced from donor cells, and
telomere length will be determined by quantitative PCR. We will use adjusted Cox proportional hazards
models to evaluate the links between donor telomere length or genotype and post-transplant survival time.
Novel genotypic associations with telomere dysfunction will be validated in vitro. These findings will help
distinguish the contributions of innate and acquired telomere dysfunction to poor post-transplant outcomes.
Study Aim 2 will test the association between short allograft epithelial cell telomeres and CLAD-free survival
in a longitudinal cohort. Epithelial telomere lengths will be determined by fluorescence-in situ hybridization
with a telomere-specific probe (Telo-FISH) on endobronchial and transbronchial biopsy tissues. We will test
the association between telomere length and CLAD-free survival using adjusted Cox models and examine
transcriptomic sequelae of telomere dysfunction. In Study Aim 3, we will determine whether airway epithelial
cell injury is associated with allograft telomere shortening and epigenetic aging in a prospectively enrolled
cohort of lung transplant recipients. Early allograft injury will be assessed clinically by the presence of primary
graft dysfunction (PGD). We also quantify allograft e...

## Key facts

- **NIH application ID:** 10013614
- **Project number:** 1I01CX002011-01A1
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** JOHN GREENLAND
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013614

## Citation

> US National Institutes of Health, RePORTER application 10013614, Accelerated Aging as a Cause of Chronic Lung Allograft Dysfunction (1I01CX002011-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10013614. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*