# Pulmonary Fibrosis and Telomerase Dysfunction

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $718,821

## Abstract

ABSTRACT
Unbiased genomic approaches have led to discoveries of novel disease genes and variants. Most pathogenic
rare variants found in patients with Familial Pulmonary Fibrosis (FPF) and Idiopathic Pulmonary Fibrosis (IPF)
result in telomere shortening. Thus, these diseases are part of the spectrum of diseases known as
telomeropathies or short telomere syndromes. Telomere lengths of peripheral blood cells predict clinical
outcomes of IPF patients, including survival, rate of disease progression, and response to certain medications.
A larger proportion of FPF and IPF patients have evidence of telomere shortening than are explained by
genetic mutations. This study seeks to use whole genome sequencing to identify genetic variants that
engender an inherited susceptibility to lung fibrosis. The underlying hypothesis of this application is that
telomerase dysfunction is a key mechanism underlying development of pulmonary fibrosis.
This application plans to evaluate whole genome sequence (WGS) data obtained for a discovery cohort of
~950 unrelated FPF probands and IPF patients. In Aim 1, we will estimate telomere length from the WGS data,
identify rare coding and noncoding qualifying variants in the telomere genes, assess genotype-phenotype
relationships, and study the return of genetic results to patients and their physicians. This aim will allow for
assessment of known telomere genes in well-phenotyped patients. Since a large portion of FPF and IPF
patients with telomere lengths <10th percentile have no identifiable telomere-related pathogenic or likely
pathogenic variant, we will utilize WGS data and five independent strategies to identify novel candidate genes:
analysis of variants by genomic location, analysis of rare variants by gene-based collapsing tests, analysis of
common variants by GWAS, analysis of variants using a sliding window test, and analysis of copy number
variants. Candidate genes and variants identified in the discovery cohort will be evaluated in replicate cohorts.
This aim has the potential to discover new genes linked to pulmonary fibrosis and telomere biology. In Aim 3,
we will explore three avenues of functional investigation: through assessment of co-segregation in informative
kindreds, through in vitro studies of gene function in patient-derived lymphocytes and other cell types, and
through evaluation of CRISPR/Cas9-engineered mouse models of disease. The latter aim will focus on
elucidating the function of PARN, a de-adenylase that has an important role in the post-transcriptional
maturation of telomerase RNA, with regard to the development of pulmonary fibrosis. Overall, this application
plans to use WGS, large FPF and IPF cohorts, as well as cutting-edge statistical analyses and experimental
approaches to extend our knowledge of the genetic architecture of pulmonary fibrosis and human telomere-
related diseases.

## Key facts

- **NIH application ID:** 10435541
- **Project number:** 5R01HL093096-12
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Christine Kim Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $718,821
- **Award type:** 5
- **Project period:** 2009-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435541

## Citation

> US National Institutes of Health, RePORTER application 10435541, Pulmonary Fibrosis and Telomerase Dysfunction (5R01HL093096-12). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10435541. Licensed CC0.

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