Notch3在肺泡再生与肺纤维化中的作用研究

特发性肺纤维化生存率低，发病率高，严重危害生命健康。研究其发病机理，开发新的治疗手段既是重要的科学问题也是迫切的医疗需求。申请人前期工作中发现特发性肺纤维化特有的蜂窝囊泡具有Notch信号活性，在小鼠肺损伤模型中Notch信号持续激活导致肺泡上皮细胞异常修复，肺泡再生失败。已知广谱抑制Notch活性引起细胞毒性，而特异靶向单个Notch受体可能可以避免毒性问题。鉴于前期工作提示了Notch3很可能参与了人和小鼠肺上皮细胞的异常修复过程，本申请计划利用小鼠肺损伤模型、谱系特异性基因敲除小鼠和类器官培养系统，结合细胞生物学、分子生物学、单细胞测序和生物信息学分析等手段，深入研究Notch3在肺上皮干细胞命运决定和肺纤维化过程中的作用，并探索新的促进肺泡再生、重建上皮屏障的调控因子，以期为肺纤维化及其他急慢性肺上皮损伤导致的疾病提供新的治疗靶点和手段。

Idiopathic pulmonary fibrosis (IPF) is a life-threatening chronic, progressive interstitial lung disease representing a huge unmet medical need. Our previous work showed Notch activity in the honeycomb cysts in IPF lungs and demonstrated in mouse model that persistent Notch signaling after severe injury leads to formation of parenchymal microscopic honeycombing, which indicates failed regeneration. As it's reported that pan-Notch inhibition leads to cellular toxicity, targeting specific Notch receptor may avoid this issue. Our work suggest Notch3 is involved in the aberrant alveolar repair in both human and mouse lungs in response to injury. Here we propose to study the role of Notch3 in lung stem cell fate determination and fibrogenesis, and explore the potential molecules to stimulate alveolar regeneration and restore barrier function using mouse lung injury models, lineage specific knock out mice, organoid culture, cellular and molecular biology and scRNAseq approaches. The ultimate goal is to provide new therapeutic targets or approaches for IPF and other lung injury related pulmonary diseases.