Project Grant R01HL181589

The National Heart, Lung, and Blood Institute awarded the University of California, Los Angeles $783,885 for Project Grant R01HL181589 on September 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837).

The award funds research on the role of NTRK2 isoforms in alveolar injury and repair related to bronchopulmonary dysplasia (BPD), a chronic lung disease affecting approximately 10,000 premature infants annually in the United States. The research employs multiomic profiling of vascular endothelial cells from control and BPD patient lungs to investigate a pathological isoform switch in the neurotrophic receptor tyrosine kinase 2 (NTRK2), driven by the splicing factor RBFOX2, that converts the full-length receptor NTRK2-FL into a truncated isoform NTRK2-T1 lacking the kinase domain. Preliminary work in hyperoxia-induced mouse models and human vascularized lung organoids demonstrates that NTRK2-FL supports alveolar and vascular regeneration, while increased NTRK2-T1 expression results in alveolar simplification, and that restoring NTRK2-FL expression through lipid nanoparticle-delivered mRNA enhances angiogenesis and reverses alveolar damage in vivo. The research plan includes three aims: defining the downstream signaling and functional roles of NTRK2 isoforms in general capillary endothelial cells; elucidating upstream regulatory mechanisms that increase NTRK2-T1 levels in response to hyperoxia; and evaluating therapeutic efficacy of NTRK2-FL mRNA delivery or antisense oligonucleotide-mediated splicing correction using vascularized lung organoids.

Work is performed in Los Angeles, California. The period of performance runs through May 31, 2030.