环状RNA通过靶向BCKDHA调控支链氨基酸介导的PCOS卵巢局部胰岛素抵抗与炎症反应发生的机制研究

Polycystic ovary syndrome (PCOS) is universally recognized as a heterogeneous disease with coexistance of reproductive malfunction and metabolic disorders, and insulin resistance (IR) is an important factor related to the disorders of reproduction and metabolism. Besides, the chronic inflammatory state of PCOS aggravates the development of metabolic abnormalities. To reveal the mechanism of insulin resistance and inflammation in the ovary of PCOS patients is the key of improving the microenvironment of follicle development. Our previous studies reported the level of branched-chain amino acid in the serum and follicular fluid of PCOS women was obviously increased, which was positively correlated with IR and the levels of inflammatory factors, indicating that BCAA could involved in the pathological process of IR and inflammation in PCOS. Moreover, we previously found the decreased expression of BCKDHA (a limiting enzyme in BCAA catabolism) in the ovarian granulosa cell of PCOS, which inhibiting the catabolism of BCAA. Furthermore, we used microarray of circular RNAs to screen a circRNA which was down-regulated in PCOS granulosa cell and targeted to BCKDHA. Thus, we proposed a research hypothesis on the regulation cascade of “circRNA→BCKDHA→BCAA catabolism→high level of BCAA→IR and inflammation”, and the aim of this study is to elucidate relevant molecular mechanisms. Our findings will be important not only in providing the theoretical basis for PCOS pathology, but also in development of potential targets for intervention.

多囊卵巢综合征（PCOS）是生殖障碍与代谢异常共存的异质性疾病，其全身及卵巢局部胰岛素抵抗（IR）是联系生殖与代谢紊乱的关键环节，同时PCOS慢性炎症状态加剧其代谢异常的发展。阐明PCOS卵巢局部IR和炎症发生机制是改善卵泡发育微环境的关键。项目组前期研究发现PCOS患者血浆和卵泡液中支链氨基酸（BCAA）水平升高，且与IR及炎症因子水平正相关，提示BCAA可能参与PCOS IR和炎症发生的病理过程。此外，前期研究发现PCOS卵巢颗粒细胞BCAA分解代谢限速酶BCKDHA表达显著下调，抑制BCAA分解；进一步通过芯片筛选出PCOS组下调并靶向调控BCKDHA的circRNA。由此，本项目提出“circRNA→BCKDHA→BCAA分解代谢→高水平BCAA→IR和炎症”层级调控假设，拟阐明相关分子机制，对于理解PCOS发病机理、拓展干预靶点具有重要意义。

多囊卵巢综合征（PCOS）是生殖障碍与代谢异常共存的异质性疾病，其全身及卵巢局部胰岛素抵抗（IR）是联系生殖与代谢紊乱的重要环节，同时PCOS慢性炎症状态加剧其代谢异常的发展。阐明PCOS卵巢局部IR和炎症发生机制是改善卵泡发育微环境的关键。项目组在前期研究基础上，围绕PCOS患者支链氨基酸代谢异常的调控作用，对环状RNA通过靶向BCKDHA基因影响BCAA分解代谢、进而调控卵巢局部胰岛素抵抗和炎症发生的具体机制进行探索。研究组确定了人卵巢颗粒细胞中调控BCKDHA基因表达的circRNA分子，明确了BCKDHA基因表达下调/活性抑制对BCAA分解代谢的影响，揭示了其对人卵巢颗粒细胞胰岛素敏感性、炎症反应、线粒体功能等的调控作用及分子途径；进一步利用动物模型阐明BCKDHA活性抑制介导的BCAA分解代谢障碍导致雌性小鼠呈现PCOS样表型特征，同时确定了通过调节BCAA水平改善PCOS卵巢功能及炎症反应的有效方法；此外，利用临床专病队列，基于支链氨基酸等标志物建立PCOS患者胰岛素抵抗发生风险预测模型。以上研究结果从支链氨基酸代谢调控机制角度，为探讨PCOS病理机制及探索相应干预策略提供理论支持。以上研究结果发表论文5篇、另2篇论文投稿中；获批发明专利3项；研究成果参与获得北京市科技进步一等奖。项目协助培养博士毕业生2名、硕士毕业生1名，研究人员参加中华医学会生殖医学分会等学术会议进行大会报告/壁报交流。