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

支气管肺发育不良(BPD)是早产儿最常见的慢性肺部疾病，发病率呈上升趋势，仍是导致发病率和死亡率的主要原因。目前，还没有根治方法可用。肺动脉高压(PH)是BPD的常见并发症，死亡率高。成纤维细胞生长因子10(FGF10)是FGFR2b受体的主要配体，也是肺发育和再生过程中的主要调节因子。在BPD的婴儿中，FGF10的表达减少。我们的初步数据表明，FGF10/FGFR2b信号在成年Fgf10/-和FGFR2b/-小鼠中的结构性缺陷导致了PH的发生。此外，出生后高氧暴露的Rosa26rtTA/；tet(O)solFgfr2b新生小鼠(BPD小鼠模型)，如果同时诱导FGFR2b信号通路的阻断，则会发生PH。我们假设PH与FGF10/FGFR2b信号通路有因果关系。为了验证这一假设，我们想要用Rosa26rtTA/；tet(O)solFgfr2b和FGFR2b/-小鼠来表征PH的发展和进展。通过对出生后第8、14、28和3月龄的超声心动图、肺功能、血流动力学测量、基因芯片、肺泡器官分析、流式细胞仪、组织学(包括血管形态计量学)和基因表达分析(qRT-PCR、单细胞转录分析)的综合分析，我们想要探讨其潜在的机制。此外，我们希望使用体内谱系追踪方法(Acta2CreERT2；tdTomatoflox和Fgf10CreERT2；tdTomatoflox)来确定Fgf10和Acta2表达的细胞在PH发生中的起源。最后，我们想要测试临床级别的重组人FGF10在新生小鼠常氧和高氧的背景下是否对PH有预防或治疗作用。我们研究的总体目标是确定FGF10是一种治疗BPD中的PH的新药。

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.