Project Summary Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease that results in lung scarring and breathing difficulty with a median survival of 2-5 years following diagnosis. Although the underlying mechanisms are poorly understood, fibroblastic foci develop around alveoli as dense regions of extracellular matrix (ECM) and activated fibroblasts and myofibroblasts. These stiff fibrotic lesions are implicated in the pathogenesis of IPF as poorer outcomes are observed in patients with more fibroblastic foci. Age is a major risk factor in IPF, and aging pathways, including the senescence-associated secretory pathway (SASP) and development of apoptosis- resistant fibroblasts, have been implicated in IPF. However, the interplay between ECM mechanosensing and aging in IPF remains poorly understood, and this lack of understanding limits the development of therapeutic agents. The objective of this project is to elucidate the contributions of FAK mechanosensing to ECM remodeling, senescence, apoptosis-resistance, and SASP in pulmonary fibrosis. Our central hypothesis is that aging- associated dysregulation of FAK mechanosignaling drives pulmonary fibrosis. We will exploit a novel in vitro 3D bioengineered microtissue model that mimics healthy and diseased lung tissue to dissect FAK mechanosignaling in senescent fibroblasts and an IPF-relevant aged mouse model to evaluate inhaled microparticles delivering FAK inhibitors in alleviating pulmonary fibrosis. Aim 1. Engineer microtissues using human primary fibroblasts isolated from IPF and healthy donors to model senescence and ECM remodeling in pulmonary fibrosis. Aim 2. Assess the role of FAK in regulating senescent phenotype, apoptosis, SASP, and ECM remodeling in NHLF and DHLF-IPF microtissues. Aim 3. Evaluate the therapeutic effects of inhaled microparticles delivering FAK inhibitor in modulating fibroblast senescence and alleviating pulmonary fibrosis in a bleomycin-induced lung injury model in aged mice. This research will provide new insights into cell-ECM interactions driving disease and identify therapeutic targets for the treatment of IPF.

Project Narrative Idiopathic pulmonary fibrosis is a chronic, progressive disease that results in lung scarring and breathing difficulty with a median survival of 2-5 years. We hypothesis that aging-associated dysregulation of mechanosignaling drives pulmonary fibrosis. We will exploit a novel in vitro 3D bioengineered microtissue model that mimics healthy and diseased lung tissue to dissect mechanosignaling in aging fibroblasts and a disease-relevant aged mouse model to evaluate inhaled microparticles delivering drugs in alleviating pulmonary fibrosis.