雌激素与miRNA协同调控子宫螺旋动脉钾离子通道在子宫腺肌症中的作用机制研究

Adenomyosis (AM) is a hormone dependent disease caused by uterine or diffuse enlargement of endometrial glands and stromal invasion of the myometrium. It can cause dysmenorrhea, menstrual volume, infertility and other serious threats to women's reproductive health. The path-physiological mechanism of AM remains unknown. Recently, we found that endometrial tissue growth orientation changes due to endometrium damage plays the major cause in AM, which was supported by National Nature Science Fund( No.30872747). Further study demonstrated that growth orientation of glands and extra matrix on endometrium completely changed from inside to outside in AM patients , in which mRNA levels of BKCa and Kv4.3 were significantly increased, and spiral artery was dilatation. In order to further elucidate cellular and molecular mechanism of AM by using AM patients samples, we proposed that abnormal expression of BKCa might be modulated by miRNA via estrogen signaling pathway. In this study, we will mainly focus on 1) miRNA directly involve transcriptions and translations of BKCa channel on spiral artery. 2) Abnormality of BCa channel function will result in spiral artery over dilated which lead to large amount of inflammatory mediator release, damage endometrium and eventually cause AM. This novel propose not only provide a new molecular mechanism for AM but also will be useful to identify new potential therapeutically targets for AM and prevention for AM.

子宫腺肌症(AM)为子宫内膜腺体和间质侵入子宫肌层所致子宫局灶或弥漫性增大的激素依赖性疾病。可致痛经、月经量多、不育等损害了妇女生殖健康。其机制不清。我们认为“子宫内膜损伤导致内膜生长极向改变是AM发生的根本原因”并获国自然基金资助（No. 30872747），发现AM内膜腺体和间质反向生长，平滑肌K+通道BKCa和Kv4.3mRNA高表达、螺旋动脉（spiral artery，SA）扩张。本研究拟结合AM患者病理标本与细胞模型开展多角度多层次的研究，构建雌激素介导miRNA调控平滑肌细胞BKCa离子通道功能紊乱的网络调控路径，阐明“雌激素和miRNA共同参与调节子宫内膜螺旋动脉BKCa离子通道，彼此关系异常，导致螺旋动脉舒缩紊乱，诱导炎性介质释放，增加子宫内膜损伤从而发生AM”这一可能机理，加深AM发病机制认知，并为将来寻找和发现新的AM治疗和预防靶点提供理论基础。

子宫腺肌症作为育龄期女性的常见疾病，其发生机制尚不清楚，缺乏有效的治疗方法。AM的诊断标准非常有限，常常诊断会延误，有的甚至长达10年之久，因此对AM发生机制的研究，对探索新的诊断标准和有效的靶向治疗具有非常重要的临床价值。维甲酸(RA)控制多种细胞类型的增殖和分化，对许多组织的发育和维持是不可或缺的，包括眼、脑、卵巢和心脏，STRA6则是子宫内膜摄取视黄醇的主要调节因子，但维甲酸通道和腺肌症的关系尚不明确。本研究探究正常患者与子宫腺肌病患者在位内膜中STRA6及CRABP2蛋白表达量，并分析子宫腺肌病与患者某些基本情况的关联；探究FASN与GSK-3β免疫荧光共定位情况和293T细胞及HAVSMC细胞中STRA6及CRABP2免疫荧光表达水平情况，并进一步探究不同浓度雌激素对293T及HAVSMC细胞中NANOG、AXIN2、LEF1、TCF4、LRP5、β-Catenin, FASN, GSK-3β表达情况的影响，以及细胞内外GSK-3β与FASN互作及p-GSK-3β与FASN互作情况，并构建动物模型，探究子宫抑制STRA6能否缓解腺肌病发生。我们的研究结果发现视黄醇的主要调节因子STRA6在腺肌症的发生发展中发挥重要作用，移植STRA6的活性可显著影响雌激素对维甲酸通道关键因子的调控。