Blurring of the Airway-Alveolar Boundary: Dissecting the Mechanism Underlying Bronchiolization

About This Grant

PROJECT SUMMARY/ABSTRACT Bronchiolization of alveoli – replacement of gas-exchange epithelium by airway-like cells – is the project’s key focus because it cripples pulmonary function in pulmonary fibrosis. The long-term goal is to identify and pharmacologically target stress- and glycosylation-driven pathways that destabilize alveolar identity, thereby advancing therapies that align with NIH’s mission to reduce morbidity from chronic lung disease. Guided by three Specific Aims, the applicant will (1) pinpoint the integrated-stress-response kinase triggering ATF4 activation, (2) determine whether ISR-ATF4 signaling is necessary and sufficient for bronchiolization, and (3) establish how ATF4-induced FUT1-mediated α1,2-fucosylation suppresses BMP4 signaling and shifts airway-alveolar cell competition. The research design combines phospho-proteomics, genetic and small-molecule kinase blockade, conditional gene deletion, lineage-traced organoids, single-cell RNA-sequencing, quantitative histology, and lung-function testing to deliver mechanistic clarity and druggable nodes. The fellowship training plan integrates advanced coursework in single-cell genomics, glycobiology, and organoid engineering with bi-weekly mentor meetings, grant-writing workshops, and LungMAP consortium bootcamps to cultivate technical breadth, analytical rigor, and leadership. The training environment – the UC San Diego Lung Center, epigenomics and imaging cores, glycobiology facility, and multidisciplinary fibrosis network – provides state-of-the-art resources, expert consultation, and a collaborative culture that will accelerate the candidate’s development into an independent investigator.