AQP5/8在病理高雌激素下介导宫腔液体过量分泌及异常植入的功能和机理研究

The accurate secretion and reabsorption of uterine fluid during preimplantation which was strictly regulated by steroid hormones, was very important for embryo implantation. However, the critical molecular which might play an important role in this process is still unknown. In previous study we found that the pathological hyper-estrogen during preimplantation could increase the expression of two aquaporins AQP5 and AQP8 in the uterus, which was accompany with aberrant increase of uterine fluid and decent of embryo implantation. Considering the importance of AQPs in fluid transport, we speculated that AQP5/8 regulated by estrogen may act as the direct molecules to regulate the uterine fluid secretion and the increase of their expression was important for implantation. In this study, we will use aqp5 and aqp8 knockout mice to demonstrate this hypothesis in the hyper-estrogen model, and to figure out the estrogen regulation of AQP5/8 by estrogen repressor and estrogen receptor α/β knockout mice. We also will try to change the expression of AQP5 and AQP8 to rescue the adverse effect of uterine fluid homeostasis and implantation by exogenous progesterone treatment. This study will help to clarify the regulation of uterine fluid and provide the theoretical and therapeutic basis to endocrine disturbance caused uterine fluid ascension and implantation fail in clinic practices.

胚胎植入前，宫腔液体的准确分泌与重吸收受母体激素的严格调控，是胚胎宫内准确定位及植入的前提，然而有关其调控的分子机制尚不明确。申请人在前期研究中发现: 植入前病理剂量的雌激素能够显著上调子宫中水通道蛋白AQP5、AQP8的表达，同时伴有植入前宫腔液体异常增多、植入率显著下降及胚胎定位紊乱。鉴于水通道蛋白在水转运中起重要作用，我们推测AQP5/8可能是介导高雌激素下宫腔液体过量分泌、进而导致异常植入的关键分子。为证明此假设，本课题拟通过AQP5/8敲除鼠在高雌激素病理模型中研究其在植入前宫腔液体分泌中的作用及对植入的影响；通过雌激素受体阻断剂及受体敲除鼠等手段探讨AQP5/8在雌激素下的调控机制；并尝试能否通过外源性孕酮降低AQP5/8的表达以改善高雌激素对宫腔液体及植入的不良影响。本研究旨在阐明宫腔液体分泌的分子调控机制，为临床内分泌紊乱导致的宫腔液体异常和植入率下降提供新理论和治疗依据。

胚胎植入前宫腔液体介导了胚胎和子宫的对话，是胚胎宫内准确定位及正常植入的前提。其准确的分泌与重吸收受母体激素的严格调控，然而有关其调控的分子机制尚不明确。本项目利用小鼠模型研究发现植入前病理剂量的雌激素能够导致植入前宫腔液体异常增多、植入率显著下降及胚胎定位紊乱。基因芯片分析发现高雌激素导致子宫中水通道蛋白AQP5、AQP8的表达显著上升，并且敲除AQP5/8能有效缓解高雌激素的影响，降低宫腔液体分泌，提高胚胎植入率。通过去卵巢小鼠模型检测发现AQP5和AQP8表达受雌激素呈现时间依赖性变化，主要依赖ERα信号通路。通过外源添加孕酮，能降低AQP5/8的表达改善高雌激素对宫腔液体及植入的不良影响。本研究阐明了宫腔液体分泌的分子调控机制，为临床内分泌紊乱导致的宫腔液体异常和植入率下降提供了新理论和治疗依据。