p66shc调控PCOS卵巢纤维化病理的机理研究

Polycystic ovary syndrome (PCOS), one of the most common and most complex female endocrinal diseases, is refractory to curative treatment due to lack of understanding about its etiology. Chronic inflammation and oxidative stress have recently been recognized as important components in the pathophysiology of PCOS, with the former being the most important factor that may lead to fibrosis. Previously, we found that DHEA-induced PCOS rats exhibited a high level of fibrosis in both ovarian and uterine tissues, which could be partially reversed by drugs such as metformin. Therefore, we speculate that in PCOS patients/animals, higher levels of local (ovarian and uterine) fibrosis and local and systemic oxidative stress (mediated by p66Shc) may exist. Fibrosis and oxidative stress might interact with each other, thus leading to anovulation and a higher rate of pregnancy loss in PCOS patients. In this project, we intend to explore the hypothesis and determine the mechanisms involved, and to develop therapeutic strategies to improve the function of ovaries/uteri of PCOS patients by inhibiting fibrosis or oxidative stress.

多囊卵巢综合征（PCOS）是最常见、最复杂的女性生殖内分泌疾病，临床主要表现为生殖激素紊乱，生殖功能障碍及糖代谢异常。其病因不明,最近文献表明，卵巢慢性炎症和氧化应激可能是PCOS病理进程的重要组成部分。我们的研究显示：PCOS动物模型存在以卵泡为中心的肌成纤维细胞增生和组织纤维化，是PCOS卵泡发育障碍，排卵受阻可能的原因。这种特征性组织纤维化起因虽不明确，但提示可能与卵泡发育异常有关。我们假设，与卵泡发育密切相关的TGF-β家族信号分子，如GDF-9和BMP-15等，因局部炎症和氧化应激过度激活，通过p66shc诱发或加重卵巢局部组织纤维化。我们提出，针对卵巢氧化应激和组织纤维化病理特征进行研究，确定其主要信号通路，为疾病药物干预，提供依据。

多囊卵巢综合征（PCOS）是最常见、最复杂、难以治愈的女性生殖内分泌疾病，病因不明。最近文献表明慢性炎症和氧化应激可能是 PCOS 病理进程的重要组成部分。我们研究发现PCOS存在卵泡周围肌成纤维细胞增多、过度纤维化，提示纤维化可能是PCOS卵泡发育障碍的原因之一；我们以DHEA诱导的PCOS大鼠、颗粒细胞为研究对象，在体内、体外两个水平证明了PCOS时同时存在卵巢纤维化和氧化应激（OS）的病理现象，并阐明了卵巢纤维化是TGF-β/Smad依赖和卵母细胞—颗粒细胞—膜细胞旁分泌紊乱参与的，而OS是p66shc依赖的机制，并且OS对纤维化有促进作用。针对PCOS时纤维化和OS两种重要病理现象，采用药物逆转纤维化和Sirt1激动剂抑制OS的方法对PCOS卵巢形态学及功能（排卵）具有积极的作用，为后续的研究与临床应用提供初步依据。