Unraveling the molecular origins of chronic parenchymal lung diseases

PROJECT SUMMARY: Single-cell genomic studies have transformed our understanding of the cellular organization and plasticity of the human lung, providing substantial insights into molecular pathways active in end-stage lung diseases including pulmonary fibrosis (PF), bronchopulmonary dysplasia (BPD) and others. A

common theme emerging across these studies is that there is a profound loss of highly specialized cells and cellular phenotypes in advanced lung diseases. The critical signals responsible for tissue organization and cellular specialization during lung development occur in three-dimensional space, and spatial context is critical

to understand the intercellular communication mechanisms, and relationships among different cell types and states that establish and maintain distal lung “niche specialization”. These observations lead us to hypothesize that perturbations of cell-cell signaling in the alveolar niche lead to loss of cellular specialization,

and disease-specific programs of progressive pathologic remodeling in PF, BPD and other chronic lung diseases. The goal of this LungMAP3.0 Research Center is to identify key molecular targets at the early stage of disease most amenable to stabilization or reversal. Our specific aims are to: 1) Develop a spatially-resolved

molecular atlas of chronic parenchymal lung diseases, 2) Define mechanisms of niche dysregulation that result in the progressive histopathologic patterns of chronic lung diseases across the lifespan and 3) Investigate the transcriptional regulatory mechanisms through which niche-perturbations promote and prevent disease

progression. We have assembled a team of investigators with a strong history of productive collaboration who offer expertise in chronic lung diseases that manifest across the lifetime and share a deep commitment to rapid and transparent data sharing in support of the lung biology community. We are excited to partner with other

LungMAP Research Centers, the Data Coordinating Center and Human Tissue Core as we leverage state-of- the-art single-cell and spatial transcriptomic approaches that enable interrogation of archival samples from highly unique cohorts of early-stage lung disease as we investigate the molecular origins of alveolar niche

dysregulation in IPF, other forms of interstitial lung disease, and BPD.