PROGRAM PROJECT SUMMARY To develop novel, transformative therapies that substantially reduce the burden of morbidity and mortality from progressive pulmonary fibrosis (PF), a fundamentally new conceptualization of PF is required. It is becoming clear that lung fibrosis is a consequence, rather than the primary driver, of disease pathobiology and represents the culmination of a lengthy period of pre-clinical disease progression driven by repetitive cycles of epithelial injury and dysfunctional repair. Rather than focusing on slowing progression of established PF, we propose that therapeutic efforts should be directed at preventing the development of symptomatic PF. This Program will focus primarily on the pre-symptomatic period, which represents the ideal time for interventions to modify the course of PF. Our overall objective is to re-shape understanding of the natural history of PF by investigating the transcriptomic, genetic, epigenetic, metabolic, and exposome-related signatures that contribute to disease initiation and early progression. Our long-term goals are to use the knowledge gained in this Program to develop new strategies for pre-clinical risk stratification and to identify novel approaches for disease prevention and treatment. This Program consists of 4 Projects and 3 Cores and will leverage our ongoing cohort study of asymptomatic relatives of patients with familial PF (FPF). Project 1 titled “Mechanisms of Early Disease Progression in FPF” will investigate single-cell transcriptomics from blood and bronchoalveolar lavage cells to identify critical mechanisms driving pre-clinical FPF and develop better biomarkers for identification of early disease. Project 2 titled “Environmental Exposures in Pre-Clinical FPF” will use cutting-edge technology combined with standardized assessments to measure real-time exposures and identify specific environmental toxins that contribute to the early development of PF. Project 3 titled “Functional genomic mechanisms of epithelial dysfunction in Pulmonary Fibrosis” will utilize single-cell multiomics from lung biopsies and patient-derived organoid models to investigate the mechanisms through which genetic factors interact with environmentally-driven stimuli to drive the initiation and progression of PF. Project 4 titled “Defining the molecular natural history of early and progressive pulmonary fibrosis” will utilize state-of-the-art spatial transcriptomic technologies and ex vivo culture models to generate a spatially-resolved molecular atlas of pre-clinical and progressive PF. The Administrative Core houses expertise to manage and support the entire program, the Clinical and Biospecimen Core will conduct all studies involving human subjects, and the Genomics Core will support data acquisition, analysis, storage, and dissemination. Together, we anticipate that the highly-integrated and synergistic nature of this proposal will result in a revolution in understanding of early PF pathogenesis and facilit...