# Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $92,830

## Abstract

PROJECT SUMMARY OF PARENT GRANT:
Lung transplantation is a potentially lifesaving option for patients with end-stage lung diseases, such as
idiopathic pulmonary fibrosis (IPF). However, the median survival following lung transplantation is less than six
years, limited primarily by chronic lung allograft dysfunction (CLAD). Emerging data suggest that dysfunction of
telomeres, the nucleoprotein caps that protect chromosomes during cellular replication, can result in IPF. It is
unknown whether telomere dysfunction also plays a role in CLAD. Were that to be the case, the same
pathophysiology that necessitated transplant might also underlie its failure. Our preliminary data show that
shorter telomeres in peripheral blood of lung allograft donors predict decreased survival in lung allograft
recipients. We also have found that telomere dysfunction in airway progenitor cells is sufficient to induce the
pathologic hallmarks of CLAD in an experimental murine model. In humans, progenitor cells such as type II
alveolar epithelial cells (AEC2) can proliferate and differentiate to restore epithelial integrity following injury.
Thus, AEC2 failure, driven by telomere dysfunction, could lead to denuded alveolar epithelium that is replaced
by fibrotic tissue. With the support of this award, we will test the innovative hypothesis that telomere
dysfunction is a molecular driver of 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, 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 CLAD-free survival time. 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 AEC2 telomeres and CLAD-free survival in a longitudinal cohort. AEC2
telomere length will be determined by fluorescence-in situ hybridization with a telomere-specific probe (Telo-
FISH) on transbronchial biopsy tissues co-labeled with the AEC2 maker, surfactant protein C. We will test the
association between AEC2 telomere length within the first 60 days post-transplant and CLAD-free survival
using adjusted Cox models. This aim will directly assess the link between early AEC2 telomere dysfunction
and CLAD. In Study Aim 3, we will determine whether transplant-associated lung injury and lymphocytic
inflammation are associated with time to CLAD, using a novel murine model of telomere-mediated CLAD
pathology. Overall, this proposed investigation has the potential to challenge our conceptual understanding of
CLAD and inform cutting edge therapeutic interventions. Establishing telomere dysfunction as a molecular
driver of CLAD would be new paradigm, potentially...

## Key facts

- **NIH application ID:** 10772852
- **Project number:** 3R01HL151552-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JOHN GREENLAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $92,830
- **Award type:** 3
- **Project period:** 2023-08-25 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772852

## Citation

> US National Institutes of Health, RePORTER application 10772852, Telomere Dysfunction as a cause of Chronic Lung Allograft Dysfunction (3R01HL151552-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10772852. Licensed CC0.

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