ABSTRACT This is an adminsitrative supplement request meant to expand the the scope of the parent award “Functional Interrogation of a Novel SCGB3A2+/SFTPB+ Cell in the Human Airway” (R01 HL166139). In the parent award, we describe the discovery of a new cell population, defined by a unique gene expression profile (SCGB3A2HI/SFTPB HI/CFTRHI), lacking markers for other recognized cell types such as club cells (SCGB1A1) and ionocytes (FOXI1). We termed these as Lower Airway Progenitor (LAP) cells due to their location within the lung, and preliminary data suggesting that these cells can serve as a progenitor cell. Our hypothesis, guided by preliminary data, suggested that LAP cells differentiate as early airway progenitor cells distinct from TP63+ progenitor cells and give rise to a unique subset of airway cell types. The administrative supplement aims to extend the scope of the project by identifying the transcription factors (TFs) necessary for LAP cell differentiation and maintenance, using multimodal datasets and computational tools (Aim 1). Following identification of LAP-enriched TFs, we aim to investigate the function of LAP cell-enriched TFs using genetic loss-of-function via CRISPRi. The outcome of this project will provide foundational insights into the regulation, function, and differentiation of this newly identified LAP cell population, contributing to the broader understanding of human lung biology.