KAT4乙酰化修饰介导色氨酸-犬尿氨酸代谢异常调控PCOS患者卵巢颗粒细胞炎症反应及线粒体损伤的作用机制研究

多囊卵巢综合征(PCOS)是生殖障碍和慢性炎症共存异质性疾病。课题组前期发现PCOS颗粒细胞中炎症因子上调、线粒体损伤，影响卵成熟，但具体机制尚不明确。代谢组学分析发现PCOS组卵泡液中色氨酸-犬尿氨酸代谢异常，代谢物犬尿氨酸(KYN)水平升高、犬尿喹啉酸(KYNA)水平降低，并与炎症状态密切相关；同时PCOS颗粒细胞中催化KYN生成KYNA的KAT4蛋白乙酰化水平显著升高，其酶活性可能抑制。结合工作基础和研究报道，本项目拟深入探索KAT4乙酰化介导色氨酸-犬尿氨酸代谢异常调控颗粒细胞炎症及线粒体损伤的分子机制。通过临床样本、体外细胞模型和动物模型，明确KAT4高乙酰化对其酶活性的调节，阐明KYN/KYNA水平失衡调控炎症反应和线粒体损伤的正反馈分子环路，阐释KYNA处理改善卵巢局部炎症及线粒体损伤状态并提高生殖功能的效果及作用机制，为拓展PCOS发病机理、发现新型干预靶点提供理论依据。

Polycystic ovary syndrome (PCOS) is universally recognized as a heterogeneous disease with coexistance of reproductive disorders and chronic inflammation. In the previous research, we found the up-regulation of inflammatory factors and mitochondrial dysfunction in the ovarian granulosa cells of PCOS patients, affecting the oocyte maturation, but the mechanism remains unclear. Moreover, based on the metabolomics analyses of follicular fluid, we found obvious metabolic abnormality of tryptophan-kynurenine (TRP-KYN) pathway in PCOS group. The level of metabolite kynurenine (KYN) was increased and the level of kynurenic acid (KYNA) was decreased, which was closely related to the inflammatory state of follicular fluid. Besides, the acetylation level of KAT4, catalyzing KYN to KYNA, was increased significantly in PCOS granulosa cells compared with that in control group, indicating the enzyme activity of KAT4 might be inhibited. Thus, combined with existing research reports on the regulatory role of metabolites in TRP-KYN pathway, this project is aimed to elucidate the role and molecular mechanism of KAT4 acetylation mediated metabolic abnormality of TRP-KYN pathway in regulating the inflammation and mitochondrial dysfunction in the ovarian granulosa cells of PCOS patients. The clinical samples, in vitro cell models and in vivo animal models will be used to clarify the the regulation of KAT4 hyperacetylation on its enzyme activity, to reveal the positive feedback molecular loop of KYN/KYNA imbalance regulating the inflammation and mitochondrial dysfunction, and to confirm the effect and mechanism of KYNA treatment on improving ovarian inflammation, mitochondrial dysfunction and reproductive function. The results of this study can provide theoretical basis for expanding the pathogenesis of PCOS and developing potential targets of intervention.