雌激素调控Wnt/β-catenin信号与TGF-β的“串扰”在损伤后子宫内膜病理性纤维化发生中的研究

宫腔粘连(IUA)可导致难治性不孕,病理表现为子宫内膜上皮创伤后修复障碍导致的纤维化。雌激素调控Wnt/β-catenin促进子宫内膜上皮细胞（EEC）在内稳态的增殖,但是损伤后修复中,EEC中Wnt/β-catenin和体内雌激素信号之间存在交互失衡,我们猜测这种失衡与TGF-β的“串扰”是损伤后子宫内膜纤维化的关键。本项目利用EEC气液相培养模型,通过下述内容研究它们在IUA病理发生中的机制:(1)分析血清雌激素水平和EEC中Wnt/β-catenin信号表达在IUA中的相关性;(2) 雌激素调控EEC中Wnt/β-catenin信号的剂量和时间效应;(3)雌激素调控Wnt/β-catenin信号与TGF-β的“串扰”对EEC生物学特征的影响;(4) 制备兔IUA模型探讨损伤后雌激素作用EEC中Wnt/β-catenin信号的分子机制。本项目的完成将为雌激素治疗IUA提供理论依据。

Intrauterine adhesions (IUA) is a main cause of refractory infertility,as the result of pathological basis of fibrosis and scar from improper endometrial epithelial repair afterr injury. Endometrum epithelial cell proliferation periodical under the estrogen regulate Wnt/beta-catenin signaling on homeostasis. However,there is different influence on cell responses in the setting of homeostasis and injury for the reason of different clinical prognosis.we hypothesis that the vital influence to epithelial pathological fibrosis on acount of abnormal regulation for Wnt/beta - catenin signaling and estrogen not to mention the "crosstalk" with TGF - beta interaction. This proposal aims to explore the mechanism of estrogen-regulated Wnt/ beta-catenin in the pathogenesis of IUA by accomplishing the following 4 specific aims using an air-liquid interface culture model generated with primary human endometrial epithelial cells: (1) analyzing clinical relation of serum estrogen levels and the expression of Wnt/ beta-catenin signaling molecules of endometrial in IUA; (2) dose- and time-dependent effects of estrogen on the Wnt/beta-catenin signaling in endometrial epithelial cells; (3)impacts of interaction of estrogen and Wnt/beta-catenin signaling on the characteristics of endometrial epithelial cell biology and interstitutial property; and (4) investigating the molecular mechanism of estrogen in regulating Wnt/beta-catenin signaling of endometrial epithelial cells using a rabbit IUA model. An accomplishment of this proposal will allow us to guide estrogen treatment for IUA in clinical settings.