Friday, July 26, 2024
7/26/2024
PROJECT SUMMARY During the prior funding period, we established a single-cell transcriptomic dataset of >50 idiopathic pulmonary fibrosis (IPF) and >70 non-fibrotic control lungs, through which we defined multiple previously unrecognized and/or disease-emergent cell types and states in the human lung. These studies have provided substantial new insights into the cellular diversity and molecular pathways that are active in advanced pulmonary fibrosis, and lead us to new questions: 1) What is the antecedent biology which leads to the cellular identities and pathologic molecular programs observed in advanced disease? 2) Which are the disease-mediating, nice- specific molecular programs that lead to, characterize and emerge from the histopathologic features of disease? 3) What is the genetic and molecular basis that underlies the heterogeneous outcomes among patients with progressive PF? Our preliminary data lead us to conceptualize that progressive PF is the last of three distinct stages of disease evolution, starting from a point of sub-radiographic molecular pathology through progressive radiologically detectable presymptomatic disease, culminating in progressive, symptomatic PF, and yet currently available therapies target end-stage disease mechanisms. We posit that therapeutic efforts should be directed at molecular mechanisms underlying disease initiation and progression, but prior efforts the ability to deeply interrogate the very earliest disease mechanisms has been limited by the fundamental challenge of identifying and obtaining lung tissue samples from individuals in the preclinical, presymptomatic and early stages of disease in order to link molecular pathology to subsequent disease biology and outcomes. We are now uniquely positioned to overcome both of the fundamental challenges in the field. Our central hypothesis is that distinct niche-specific, spatially-coordinated molecular programs evolve asynchronously within the lung to drive the heterogeneous progression outcomes of pulmonary fibrosis patients. Leveraging unique access to lung tissue samples from preclinical and early-stage PF subjects that are linked to genotype data and future clinical outcomes, together with formalin-fixed, paraffin- embedded (FFPE)-capable, state-of-the-art single-cell and spatial transcriptomic technologies, in the studies proposed below we will 1) Identify the cellular and molecular programs of early disease pathogenesis of PF, 2) Determine the spatial regulation and coordination of pathologic molecular programs across the natural history of PF, and 3) Define the cell-type specific genetic regulation underlying disease progression heterogeneity in pulmonary fibrosis. Together, these studies will establish an integrated understanding of the mechanisms that predict and mediate future PF biology, establishing targets and outcomes for primary and/or secondary prevention studies of PF using precision therapies.
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