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The Role of NTRK2 Isoforms in Alveolar Injury and Repair

Award Number: R01HL181589
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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The Role of NTRK2 Isoforms in Alveolar Injury and Repair - PROJECT SUMMARY Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in premature infants, affecting nearly 10,000 newborns annually in the United States. It is characterized by impaired alveologenesis, arrested vascular development, and endothelial cell dysfunction, with no curative therapy available. Although disrupted pulmonary angiogenesis is a hallmark of BPD, the molecular mechanisms governing endothelial injury and regeneration remain poorly defined. Using multiomic profiling of vascular endothelial cells from control and BPD patient lungs, we identified an expansion of general capillary endothelial cells (gCap) with aberrant expression of neurotrophic receptor tyrosine kinase 2 (NTRK2). We discovered a pathological isoform switch, driven by the splicing factor RBFOX2, that converts the full-length receptor NTRK2-FL, which promotes angiogenesis and alveolar regeneration, into a truncated isoform NTRK2-T1 that lacks the kinase domain and impairs vascular repair. In hyperoxia-induced mouse models, NTRK2-FL supports alveolar and vascular regeneration, whereas increased NTRK2-T1 expression results in persistent alveolar simplification resembling severe human BPD. Restoring NTRK2-FL expression through lipid nanoparticle delivered mRNA enhanced angiogenesis in human vascularized lung organoids and reversed alveolar simplification in vivo. We hypothesize that mis-splicing of NTRK2 in gCap cells leads to endothelial dysfunction and impaired alveolar repair after severe hyperoxic injury. To test this hypothesis, Aim 1 will define the downstream signaling and functional roles of NTRK2 isoforms in gCap cells; Aim 2 will elucidate the upstream regulatory mechanisms that increase NTRK2-T1 levels in response to hyperoxia; and Aim 3 will evaluate the therapeutic efficacy of NTRK2-FL mRNA delivery or antisense oligonucleotide (ASO) mediated splicing correction using vascularized lung organoids and mouse models of BPD. Completion of these studies will reveal a novel endothelial splicing mechanism that controls vascular regeneration and provide a strong preclinical foundation for developing isoform specific RNA therapies with high translational potential to improve outcomes in infants with BPD and related pulmonary vascular diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $783,885 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Lung Diseases Research	000	1	8/13/2026	NEW	$783,885
														Subtotal = $783,885

Grand Total All Awards = $783,885

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The Role of NTRK2 Isoforms in Alveolar Injury and Repair

Award Number: R01HL181589

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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