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.