NLRP1炎症小体调控多囊卵巢综合征患者卵巢颗粒细胞炎症反应和代谢紊乱的作用机制研究

Polycystic ovary syndrome (PCOS) is universally recognized as a heterogeneous disease with coexistance of reproductive malfunction and glucose and lipid metabolic disorders. The definition and the pathogenesis of PCOS remain unclear. At present, increasing evidences support that PCOS is a proinflammatory state, and the presence of chronic low-grade inflammation is relevant to the development of metabolic diseases, such as diabetes mellitus and cardiovascular disease. Our previous studies reported the mitochondria dysfunction and activation of inflammatory response in granulosa cells and abnormal levels of metabolites in follicular fluid of PCOS patients, which indicating the microenvironment of inflammation and metabolic abnormality in the PCOS follicles. Inflammation and metabolic disorder have now emerged as key contributor to the pathogenesis of PCOS. NLRP inflammasome functions as an intersection connecting the inflammation and metabolic process in the body. Our previous finding showed the significantly increased expressions of NLRP1 and the downstream signaling molecules in the PCOS granulosa cells, so we speculate that NLRP1 inflammasome may be activated and play a central role in mediating the inflammation and metabolic process in granulosa cells. In this study, we further investigate the role and molecular mechanism of NLRP1 inflammasome-mediated inflammation and metabolic disorder in granulosa cells of patients with polycystic ovary syndrome. Our findings will be important not only in providing the theoretical basis for PCOS pathology, but also in promoting the research and development of new treatment strategy of PCOS women.

多囊卵巢综合征（PCOS）是生殖功能障碍与糖、脂代谢异常共存的一种异质性疾病，目前对其发病原因仍不清楚。近年研究发现PCOS中存在慢性炎症，炎症与代谢性疾病的发生有着密切关系。本研究前期发现PCOS颗粒细胞中线粒体功能受损、炎症信号激活，卵泡液中代谢产物水平异常，表明PCOS卵泡炎性和代谢紊乱微环境，可能影响卵母细胞发育和成熟，然而对其机制尚未阐明。NLRP炎症小体是连接机体炎症反应与代谢过程的交接点。课题组前期研究发现PCOS颗粒细胞中NLRP1及下游信号分子表达显著上调，推测NLRP1炎症小体可能激活并作为中心调控因子调节颗粒细胞的炎症和代谢反应。因此，本研究拟从分子、细胞、动物模型多个层面，对NLRP1炎症小体调控PCOS颗粒细胞炎症和代谢紊乱的作用机制进行探索，为PCOS病理机制及干预策略提供依据。为PCOS病理机制提供理论基础，并推动PCOS干预新策略的研发。

PCOS是育龄女性最常见的生殖内分泌疾病，是一种复杂的生殖功能障碍、代谢异常与慢性炎症状态共存的异质性疾病，目前对其发病原因仍不清楚。由于NLRP炎症小体是连接机体炎症反应与代谢过程的交接点，本项目基于前期工作基础以炎症小体激活为切入点，探索PCOS的发病机制和干预靶标。研究证实了PCOS卵巢局部炎症小体的激活及炎症因子水平的显著上调；同时结合临床队列和样本分析，明确了游离脂肪酸作为上游分子激活炎症因子。PCOS卵泡液中多种游离脂肪酸水平显著升高，且游离脂肪酸介导的脂肪胰岛素抵抗影响PCOS的代谢紊乱及炎症。进一步在细胞水平上证明PCOS卵巢局部脂肪酸代谢异常可以在基因转录水平及蛋白翻译后修饰两个层面影响卵巢颗粒细胞炎症反应：油酸体外刺激卵巢颗粒细胞，一方面激活炎症小体，上调IL-18成熟体加工；另一方面可以激活ERK1/2等炎症相关通路，引起IL-6和IL-8转录上调。这一发现为揭示PCOS卵巢局部代谢-炎症相互调控作用机制提供了新方向。此外，研究团队构建PCOS-iPS细胞，提供了一个体外研究PCOS特性的细胞模型，可利用该模型后续进一步了解炎症小体激活调控PCOS炎症及代谢紊乱的病理学和开发新的潜在治疗途径。成功构建 PCOS 样动物模型，并进一步分析其子代表型变化情况，为后续进行干预的有效性和安全性评估提供子代表型分析的重点方向。以上研究结果已发表论文8篇，1篇论文已完成撰写、投稿。项目协助培养博士毕业生3名，研究人员6人次参加国际生殖医学年会、国内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。