Map the human airway basal cell niche and the role that FGFR2 plays within it

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Project Summary/Abstract Chronic obstructive pulmonary disease (COPD), asthma, primary ciliary dyskinesia (PCD) and cystic fibrosis (CF), represent airway diseases caused by complex interplay of genetic and environmental factors. They are a major cause of morbidity and mortality and effective therapies are variable. The heterogeneity of asthma and COPD and the rarity of PCD and CF pose significant challenges to their study. Despite differences in their pathogenesis these airway diseases have in common coordinated responses that involve crosstalk between epithelial, mesenchymal, and immune cells that eventually leads to airway remodeling [2]. Fundamental to this remodeling are basal cells (BCs), the major stem cell of the airway, and their niche [3]. Genetic mouse models suggest that Fgf ligands secreted by adjacent mesenchyme bind to epithelial Fgfr2 receptors to maintain BCs [4][5]. In response to injury, Fgf coordinates with Hippo and Wnt7b in an epithelial-mesenchymal signaling network to achieve epithelial regeneration [6]–[8]. Is FGFR2 signaling important in human BCs? Surprisingly, despite the importance of this question, little is known. We will test the following hypothesis: FGFR2 signaling is essential in maintaining the self-renewal capability of the human adult airway basal cell. In aim 1, we will define the basal cell niche in the human trachea and intercartilagenous airways using spatial transcriptomics, ligand-receptor signaling analyses and in situ hybridization techniques. In aim 2, we will test that FGFR2 signaling is essential in maintaining human adult airway basal cells using human primary and induced pluripotent stem cells derived BCs equipped with gene editing technology. At the conclusion of this aim we have determined the importance of FGF in maintaining the BC program. Though this represents an ambitious project in short timeframe, the tools, cells, protocols, tissue samples, and collaborators with appropriate expertise, are all in place. The scope and goals of this project will expose me to a wide variety of techniques suitable for an F32 candidate. Ultimately, this grant will generate exciting, novel data with which I can move forward into the next stage of my career as a physician-scientist studying lung biology.