Research Description

One of the major goals of LungMAP3 is to extend the growing knowledge of cellular heterogeneity within the human lung towards defining the spatial, molecular, and cellular changes that occur in human respiratory diseases. The ability to interrogate both rare and common lung disease will allow for the rapid advances of the molecular pathogenesis of these diseases and identify novel therapeutic targets. Findings from such studies will need further validation using new models of human lung cell biology including organoids and ex vivo explants. This will entail the acquisition of human adult lung samples, both normal and diseased, extending beyond what has already occurred as part of the LungMAP Consortium. The University of Pennsylvania LungMAP Center will focus on three emerging concepts and challenges: 1) accurately and precisely phenotype adult human lung diseases at the spatial and single cell level with a focus on COPD, ILDs and more rare diseases including alpha-1 anti-trypsin deficiency (A1AT), 2) identify molecular defects in progenitor cell niches in human chronic lung diseases (CLDs) through dynamic integration of single cell analytics with spatial resolution technologies to elucidate disease progression signatures, and 3) develop and implement new model assay systems to mechanistically define molecular and cellular defects during the progression of CLDs. This will require the use of advanced transcriptomic, epigenomic, and bioinformatic approaches to phenotyping cell-cell communication and cell-niche interactions. The Penn LungMAP Research Center has an existing pipeline to acquire normal and diseased lung tissue, and we have developed extensive informatic software to interrogate changes in cell fates and states in disease from deep spatial and single cell analysis. The Penn LungMAP Research Center has been extremely productive in LungMAP Phase 2 and has defined new cell lineages such as RASCs in the human lung, defined novel aspects of emphysematous disease pathology including COPD, and begun to define rare CLDs such as A1AT at a single cell level. The overarching strategy of the Penn LungMAP 3 Research Center is to phenotype the cellular and molecular changes that occur in CLDs at the single cell level and identify the mechanisms that drive CLD progression using novel approaches to integrate progenitor cell niche regulation using carefully validated ex vivo model systems.