基于子宫线粒体功能受损的PCOS生殖障碍及苍附导痰汤的疗效机制研究

PCOS is a life-long endocrine disorder that affects approximately 4%‒18% of all reproductive-aged women in the world. Insulin resistance (IR) is an inherent feature of PCOS. It is a key problem that lower pregnancy rates and higher miscarriage rates in the treatment of PCOS after ovulation induction. Endometrial dysfunction play an key role during the onset of miscarriage within PCOS patients. we have recently demonstrated that PCOS-like rats display uterine insulin resistance. Thus, it is likely that uterine insulin resistance affects uterine functions and develops higher miscarriage ratio in PCOS. Mitochondria as molecular platforms integrate multiple cellular signaling pathways, and we propose that defective regulation of these processes might be one of the underlying mechanisms of miscarriage observed in PCOS patients. Collectively our data reinforce the notion that mitochondrial defects, elevated inflammation are associated with abnormal uterine morphology in rats under conditions of insulin resistance.We also seek to understand the relative contribution and relevance of increased mitochondrial-mediated ROS production, elevated inflammation, and altered implantation-related marker levels to the mechanisms behind insulin resistance and uterine dysfunction by constructing PCOS miscarriage animal model and cell model with uterine IR, and explores the relationship between IR and PCOS miscarriage, and investigates the pathological mechanism in vivo and in vitro. CFDTT (cangfudaotantang) appears an significant advantage in PCOS treatment, but, what is the effect mechanism are uncertain. In current study, we treat the animal/cell model of uterine IR with CFDTT and elucidated what is the mechanism during the process. It will supply a scientific evidence to PCOS treatment using CFDTT.

PCOS影响世界4%-18%的育龄期女性，是严重影响“女性一生”的生殖健康疾病。胰岛素抵抗(IR)是PCOS固有特征。PCOS 促排卵后低妊娠率高流产率是PCOS治疗难点之一。子宫内膜功能障碍可能是引起PCOS反复流产的主要原因，课题组发现PCOS大鼠存在子宫IR，严重影响子宫内膜形态及功能，可能是导致PCOS高流产率原因之一。线粒体作为分子平台可整合多个细胞信号通路，线粒体损伤与IR和炎症反应密切相关，子宫IR可能通过影响线粒体介导的氧化应激反应，炎症反应和着床因子表达的变化引起流产发生。故本研究构建PCOS IR流产动物模型与子宫IR细胞模型，从体内体外探讨IR与PCOS流产发生的关系及病理机制。中药经方“苍附导痰汤（CFDTT）”治疗PCOS习惯性流产临床效果明确，但其疗效分子机制尚不清楚，本研究给予模型动物/细胞CFDTT治疗，探讨其疗效机制，为CFDTT临床应用提供科学依据。

PCOS影响世界4%-18%的育龄期女性，是严重影响“女性一生”的生殖健康疾病。胰岛素抵抗（IR）是PCOS固有特征。PCOS促排卵后低妊娠率高流产率是PCOS治疗难点之一。子宫内膜功能障碍可能是引起PCOS反复流产的主要原因，课题组发现PCOS大鼠存在子宫IR，严重影响子宫内膜形态及功能，可能是导致PCOS高流产率原因之一。线粒体作为分子平台可整合多个细胞信号通路，线粒体损伤与IR和炎症反应密切相关，子宫IR可能通过影响线粒体介导的氧化应激反应，炎症反应和着床因子表达的变化引起流产发生。故本研究构建PCOS IR流产动物模型与子宫IR细胞模型，从体内体外探讨IR与PCOS流产发生的关系及病理机制。中药经方“苍附导痰汤（CFDTT）”治疗PCOS习惯性流产临床效果明确，但其疗效分子机制尚不清楚，本研究给予模型动物/细胞CFDTT治疗，探讨其疗效机制，为CFDTT临床应用提供科学依据。研究结果表明：1.高雄-IR是引起PCOS妊娠大鼠子宫线粒体功能障碍的主要原因，并导致妊娠子宫氧化和抗氧化应激反应之间的失衡。2.首次提出了PCOS相关的高雄激素和IR对糖皮质激素受体（GR）异常信号的重要性，这些信号与线粒体功能和稳态的调节及NFκB调节的大鼠卵巢和子宫炎症有关。3.苍附导痰汤对妊娠早期子宫IR所致流产具有抑制作用。