Developing an exosomic signature of rapidly progressive idiopathic pulmonary fibrosis - PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a chronic form of interstitial lung disease with varying rates of disease progression. A subgroup of patients experience rapid IPF progression characterized by progressive respiratory failure and premature death. It is critically important to identify patients with rapidly progressive IPF early in their course to facilitate early initiation of disease-modifying interventions. Current clinical approaches to IPF prognostication including staging systems that integrate measures of lung physiology have very limited prognostic discrimination and provide no insights into the pathobiological mechanisms of IPF progression. Analyses of extracellular vesicles and their miRNA cargo (EV-miRNAs) provide a unique opportunity to improve both domains by identifying novel biomarkers of accelerated IPF progression and elucidating potentially modifiable targets for IPF treatment. Recent preclinical studies suggest alterations in plasma EV-miRNAs precede IPF progression. However, studies in human populations are limited. In this K23 Mentored Patient-Oriented Research Career Development Award, Dr. Christina Eckhardt will build upon her prior work showing plasma EV-miRNAs are robust biomarkers of early lung injury and will investigate the role of plasma EV-miRNAs in IPF progression. The central hypothesis is that adults with rapidly progressive IPF have unique plasma EV-miRNA signatures that can quantify and predict risk of accelerated IPF progression. To test this hypothesis, Dr. Eckhardt will cost-effectively leverage three prospective IPF cohorts with ready-to- use collections of blood draws, lung function data, and respiratory health outcomes data. Dr. Eckhardt will leverage these existing resources to identify EV-miRNAs that capture and quantify the intrinsic progressiveness of IPF (Aim 1), derive and validate an EV-miRNA signature that predicts accelerated IPF progression (Aim 2), and define the relationship between profibrotic gene expression in lung cells and EV-miRNA expression in plasma to corroborate EV-miRNAs as accessible biomarkers of distinct biological pathways in IPF lungs (Aim 3). To complete these aims, Dr. Eckhardt will receive expert guidance from her renowned mentoring team: Drs. Ke Cheng (Extracellular Vesicles), Christine Garcia (Interstitial Lung Disease), Elizabeth Oelsner (Respiratory Epidemiology), and Iuliana Ionita-Laza (Biostatistics). Specifically, Dr. Eckhardt will receive training in (1) extracellular vesicles and translational research methods, (2) prospective study design and conduct in adults with interstitial lung disease, (3) advanced statistical modeling, and (4) research dissemination and professional development. This career development plan will prepare Dr. Eckhardt for a career as an independent academic clinical-translational researcher who develops novel strategies to improve IPF diagnosis, optimize IPF prognostication, and deliver precision-guided interventions for adults with IPF.
