# Mitochondrial UCP2 in Age-Related Lung Fibrosis

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2020 · $168,264

## Abstract

PROJECT SUMMARY
 Aging is a major risk factor for idiopathic pulmonary fibrosis (IPF), with a marked increase in incidence and
prevalence in aged populations. Despite this strong association, cellular/molecular mechanisms that account
for the aging predilection to fibrotic disease are only now beginning to be explored. Mitochondrial dysfunction
and altered bioenergetics are common to aging and IPF. The myofibroblast (MFb) is the key effector cell in
fibrosis. Our preliminary data show that mitochondrial uncoupling protein-2 (UCP2) is increased in lung
fibroblasts (Fbs) of IPF patients, and in normal lung Fbs stimulated with TGF-β1. UCP2 silencing inhibits MFb
differentiation and senescence, decreases NADPH oxidase-4 (Nox4) expression, and reprograms metabolism
for more efficient oxidative phosphorylation with decreased glycolytic flux. Importantly, UCP2 silencing
promotes resolution of fibrosis in aged mice with otherwise persistent fibrosis. Our laboratory has shown that
Nox4 is a key mediator of MFb differentiation, senescence and resistance to apoptosis in age-related lung
fibrosis. In this grant proposal, we will test the hypothesis that induction of UCP2 during lung injury-repair in
aging contributes to bioenergetic dysfunction, sustained MFb senescence and apoptosis resistance, leading to
age-associated persistent fibrosis. Specific aims to be tested are: (1) determine the mechanisms by which
UCP2 regulates MFb differentiation and senescence; (2) determine whether UCP2-mediated bioenergetic
alterations regulate Nox4; and (3) determine whether pharmacological inhibition of UCP2, or, conditional
genetic deletion of UCP2 in collagen-producing cells/mesenchymal progenitor cells, induce(s) resolution of
fibrosis in aged mice.
 This project explores new concepts in the pathobiology of age-related lung fibrosis through the study of Fb
bioenergetics and a novel animal model. The career development plan and the research aims, combined with
a strong mentoring committee, additional training in cell and molecular biology, metabolism, and mitochondrial
biology, will meet my specific educational objectives to succeed as a young investigator. The opportunities
created by this career development award will result in my gaining the skills necessary to accurately answer
important scientific questions related to age-related lung fibrosis, successfully obtain future independent
funding, and make differences in the lives of patients affected by this devastating illness.

## Key facts

- **NIH application ID:** 9859441
- **Project number:** 5K08HL135399-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Sunad Rangarajan
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,264
- **Award type:** 5
- **Project period:** 2018-08-27 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859441

## Citation

> US National Institutes of Health, RePORTER application 9859441, Mitochondrial UCP2 in Age-Related Lung Fibrosis (5K08HL135399-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859441. Licensed CC0.

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