PROJECT SUMMARY Lung diseases impacting the gas exchange alveoli, including COVID-19, are becoming the leading cause of death. A multi-lineage, transcriptional, and epigenetic understanding of alveologenesis and re- alveologenesis upon injury is a timely response to the disease burden and leverages latest single-cell technology. My lab’s track record in studying the lung epithelial, endothelial, and mesenchymal lineages lays the foundation for pursuing a poorly understood process of cellular maturation (Theme 1), a recently identified capillary cell type (Theme 2), and a novel signaling regulation of distinct mesenchymal cell populations (Theme 3). The anticipated knowledge will tackle fundamental questions of cell fate, plasticity, and signaling; shed light on bronchopulmonary dysplasia, pulmonary hypertension, acute lung injury, as well as non-coding variants from genome-wide association studies; and opens the door to single-cell functional genomics applicable to any organ.