PGRN通过TNFR/NF-κB炎症信号通路参与PCOS卵巢局部胰岛素抵抗的机制研究

Insulin resistance in PCOS ovaries has a central role in the PCOS pathogenesis and it’s one of the current treatment difficulties. The mild chronic inflammation has been proved to mediate "cross-talk" of inflammatory signaling pathways and insulin receptor signaling pathway and been regarded as initiating factor and core areas of PCOS IR. PGRN was reported be capable of mediated hepatic insulin resistance by TNFR/NF-κB inflammatory signaling pathway .Our previous experiments confirmed PGRN highly expressed in PCOS ovarian granulosa cells, and follicular fluid PGRN levels positively correlated with TNF-α level. We hypothesize that PGRN may be involved in local ovarian insulin resistance by TNFR/NF-κB inflammatory signaling pathway. The cell model, animal model and clinical samples are used in our research. Adenovirus vector is constructed to down-regulate the expression of PGRN and TNFR/NF-κB signaling pathway in granulosa cells. The genes and proteins expression which related to inflammatory signaling pathways and insulin signaling pathway are observed . We try to illuminate the role of PGRN in ovarian inflammation and IR "cross talk" , and try to find out a strategy based on local ovarian inflammation interference for PCOS insulin resistance control.

多囊卵巢综合征（PCOS）卵巢局部胰岛素抵抗(IR)在其发病机制中具有核心作用，为目前治疗难点。慢性轻度炎症是PCOS IR始动因素和核心环节，能通过炎症信号通路与胰岛素信号通路“交叉对话”介导IR。最新研究发现PGRN能通过TNFR/NF-κB炎症信号通路诱导肝细胞IR发生。我们前期实验证实PCOS患者卵巢颗粒细胞PGRN表达增加，且卵泡液中PGRN与TNF-α呈正相关。由此假设：PGRN能通过TNFR/NF-κB炎症信号通路参与PCOS卵巢局部IR的发生。本项目拟应用细胞模型、动物模型及临床样本为研究对象，构建腺病毒载体选择性下调颗粒细胞PGRN与TNFR/NF-κB信号通路的表达，从细胞水平及动物在体水平观察炎症信号通路及胰岛素受体后信号通路蛋白和基因的表达。力图阐明PGRN在PCOS卵巢局部介导炎症及IR“交叉对话”中的作用，从卵巢局部炎症的角度为PCOS IR的治疗提供新的思路。

多囊卵巢综合征(Polycystic ovary syndrome，PCOS)是育龄期妇女最常见的内分泌和代谢性紊乱的慢性疾病，其发病机制至今不明。卵巢本身的胰岛素抵抗（IR）是PCOS发病的重要病因病机，其在PCOS发病机制中具有核心作用。炎症信号途径与胰岛素受体后信号通路异常对话是慢性炎症介导PCOS IR的分子机制， 颗粒蛋白前体（PGRN）可能参与卵巢局部慢性炎症及IR的发病机制。本项目通过临床研究、细胞实验以及动物实验验证了PGRN在PCOS发病机制中的作用。 临床研究部分比较了卵泡液中各炎性因子的表达水平组间对比，结果显示PCOS组中两组的TNF-α的表达水平均高于相应对照组，且肥胖对照组表达水平高于非肥胖对照，PGRN表达水平肥胖组均高于相应对照组，非肥胖PCOS组与非肥胖对照组相比增加。PCOS患者卵泡液中PGRN的表达水平显著升高且其水平与获卵数呈负相关，与TNF-α及睾酮水平正相关，提示提示PGRN可能作用于卵泡微环境，影响卵泡发育。细胞实验中，我们的研究结果提示PGRN能上调KGN细胞多种炎性因子包括TNF-α、IL-6、MCP-1、IL-1β等的表达，并证实其通过ERK1/2信号通路诱导卵巢颗粒细胞炎症因子及胰岛素抵抗相关因子SOCS3的表达增加，介导PCOS的慢性炎症及胰岛素抵抗发病机制。动物实验中，本研究成功建立PCOS伴IR大鼠模型，并证实了PGRN能高表达于PCOS大鼠卵巢的颗粒细胞中，且不同发育阶段卵泡PGRN的表达水平不同。本研究阐释了PCOS卵巢局部IR的病理机制，也为后续更进一步深入探索PGRN调控PCOS IR的病理机制提供支持。