7. Project Summary The primary objective of this proposal is to characterize the most important genetic and proteomic pathways that contribute to early stages of pulmonary fibrosis (PF_, with the goal of developing biomarkers for, and improving our understanding of, the initial biological processes that result in early PF pathogenesis. Idiopathic pulmonary fibrosis (IPF), the most common and severe form of PF, is increasing in prevalence, and has a mortality rate worse than most malignancies. Given that even early stages of PF may benefit from interventions there is more urgency to improve our understanding of early disease detection and to define the most important pathways that result in early stages of PF progression. In the prior grant cycle, key results helped to improve our understanding of early progressive PF, demonstrated the key genetic and genomic findings that overlap, and that are distinct from, IPF, and identified important genomic findings correlated with early stages of PF. Although these results provide important biologic signals, the predictive power of many of these biomarkers is low, and they leave important questions unanswered. We hypothesize that comprehensive proteomic and genetic assessments of ILA will lead to a better understanding of 1) the factors that best help predict disease risk, 2) the most important pathways implicated in PF development, and 3) which proteins’ secretion is increased in response to higher risk genetic profiles thus implicating their role in early PF pathogenesis. To address these hypotheses, we propose the following specific aims: Aim 1: Can peripheral blood proteins be identified that are associated with, and help to predict, early and later stages of progressive PF? Aim 2: Can polygenic risk scores (PRS) help predict early stage-stage PF and can this genetic data be integrated with proteomic assessments to improve our understanding of early PF pathogenesis? Aim 3: Can differentiated human airway epithelial cells (HAECs) demonstrate the role that high genetic risk (and environmental stimuli) play in the expression of early-stage PF associated proteins? These results will not only improve our understanding of the pathogenesis of both early and late stage PF, but will also identify candidate pathways that could lead to targets for drug development, and will identify biomarkers for future interventional trials designed to target those at the highest risk to develop IPF at a stage before the lung is irrevocably damaged.