Shh/Gli2信号通路调控子宫内膜自噬在宫腔粘连形成中的作用研究

Intrauterine adhesion(IUA) is one of the major etiology of female secondly infertility, pathologically manifesting as endometrial fibrosis, which derived from the transformation of stromal cell to myofibroblast. It has been reported the transformation of myofibroblast in other organs (lung, liver, and skin, etc) was induced by Shh signal pathway activation, and the Shh inhibited autophagy of Hela cell by transductor Gli2. We also found the remarkable overexpression of Gli2 and dropping down of LC3(symbol of autophagy) in endometrial stromal cells of IUA patients. Our other discovery was the blocker of Shh could reverse the fibrotic progress in injured murine endometrium while accelerating stromal cell autophagy through activating AMPKA phosphorylation. Next step of the research we would like to put forward is: uncovering the effect and working approach of Shh/Gli2 in autophagic vacuole formation, degradation and fusion with lysosome of stromal cell, and their subsequently affect in endometrial fibrosis, based on in vitro cell experiment, race endometrial injury model and PR-cer, Gli2f/f mouse model. The results will demonstrate our hypothesis that chronic endometrial injury activates Shh/Gli2 signal, then down regulates endometrial autophagy by inhibiting AMPKA pathway, resulting in more myofibroblast transformation and extracellular matrix deposition, finally causes endometrial fibrosis. This potential mechanism of IUA could be the basis of target therapy of this refractory disease.

宫腔粘连（IUA）主要病理表现为间质细胞向肌成纤维细胞转化引起的内膜纤维化。已有报道Shh信号通路在肝肺等脏器促成肌成纤维细胞转化，且Shh通路转录因子Gli2抑制细胞自噬。我们前期发现IUA患者内膜间质细胞中Gli2表达升高，LC3下降；动物实验中，阻断Shh能逆转损伤所致的纤维化进程；细胞实验中，Shh信号通路负向调控间质细胞自噬，其抑制作用与AMPK激活相关。因此我们提出假设：子宫内膜损伤后激活Shh/Gli2信号通路，抑制AMPK／mTOR途径减少内膜的自噬效应，进而促进间质细胞转化，加重纤维化。我们将利用内膜间质细胞、内膜损伤大鼠模型和PR-cer,Gli2f/f小鼠模型，深入研究Shh/Gli2在自噬泡生成和融合、降解中的作用途径，以及Shh－自噬在间质细胞转化和IUA形成中的作用机制和意义。

宫腔粘连（Intrauterine adhesion，IUA）是女性继发不孕的第二大病因，宫腔镜手术治疗虽然能恢复宫腔形态，但是难以恢复子宫内膜生理功能，且中重度IUA治疗后极易再粘连。因此，阐明其发生发展机制对于防治该疾病至关重要。Sonic hedgehog（shh）通路是进化保守的发育相关通路，而自噬是普遍存在细胞内的应对压力的蛋白降解途径，它们对组织修复都有重要影响，但两者如何影响子宫内膜过度损伤后的病理性修复还未可知。本研究通过临床病例-体外细胞系-小鼠宫腔粘连模型-转基因小鼠的全链条式研究，发现子宫内膜损伤后，增强的Shh信号靶向子宫内膜间质细胞，抑制细胞内自噬起始，损伤纤维化蛋白collagen I的自噬性降解，导致ECM累积，加重子宫内膜纤维化。其中，Shh通路调控自噬起始主要通过转录因子GLI2激活形式和GLI3抑制形式，并可能由pAKT-mTORC1经典调控机制所介导。本研究从调控蛋白降解角度，阐述了自噬受损参与了Shh信号驱动的子宫内膜纤维化，完善宫腔粘连的病理机制，且利用转基因小鼠证实子宫内膜间质细胞是Shh信号介导子宫内膜纤维化的效应细胞。为预防IUA、逆转难治性IUA提供了可能靶点，对其他组织器官纤维化的研究也具有一定的参考和启发价值。

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