Investigating the impact of FGF10/FGFR2b-mediated reverse remodeling of pulmonary hypertension in bronchopulmonary dysplasia - A first translational approach

• Applicant: Dr. Cho-Ming Chao
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 494828154

Bronchopulmonary dysplasia (BPD) is the most frequent chronic lung disease of prematurely born infants with rising incidence and remains a leading cause of morbidity and mortality. Currently, there is no curative therapy available. Pulmonary hypertension (PH) is a common complication in BPD, resulting in high mortality. Fibroblast Growth Factor 10 (FGF10) is a main ligand of the Fgfr2b receptor and a major regulator during lung development and regeneration. In infants with BPD, FGF10 expression is decreased. Our preliminary data showed that constitutive deficiency of FGF10/FGFR2b signaling in adult Fgf10+/- and Fgfr2b+/- mice led to development of PH. Furthermore, Rosa26rtTA/+;tet(O)solFgfr2b newborn mice exposed to hyperoxia postnatally (BPD mouse model) developed PH if blockade of FGFR2bsignaling was induced at the same time. We hypothesize that PH is causally linked to FGF10/FGFR2b signaling. In order to verify this hypothesis we want to characterize the development and progression of PH using Rosa26rtTA/+;tet(O)solFgfr2b and Fgfr2b+/- mice. Using a comprehensive panel of analyses including echocardiography, lung function, hemodynamics measurements, gene arrays, alveolar organoid assay, FACS, histology (including vascular morphometry) and gene expression analyses (qRT-PCR, single-cell transcriptomic analysis) at postnatal day 8, 14, 28 and 3 months of age, we want to investigate the underlying mechanisms. In addition, we want to use in-vivo lineage tracing approach (Acta2CreERT2; tdTomatoflox and Fgf10CreERT2; tdTomatoflox) to identify the origin of Fgf10- and Acta2-expressing cells contributing to PH development. Finally, we want to test whether clinical grade human recombinant FGF10 has a preventive or therapeutic effect on PH in the context of normoxia and hyperoxia in newborn mice. The overall aim of our study is to identify FGF10 as a new drug to treat PH in BPD.

• DFG Programme: Research Grants