Chemerin及其受体调控PCOS患者卵巢颗粒细胞增殖和凋亡的机制研究

Polycystic ovary syndrome (PCOS) is a common metabolic dysfunction and heterogeneous endocrine disorder in women of reproductive age.The main clinical characteristics of PCOS are anovulation, hyperandrogenism and insulin resistance. It was reported that glucose metabolism was impaired in ovaries of PCOS patients. Granulosa cells in PCOS ovaries were less responsive to FSH stimulation and the proliferation of granulosa cells were decreased while cell apoptosis was increased. Our previous studies found that the serum level of Chemerin, a kind ofadipokine, was significantly elevated in PCOS patients, and Chemerin level was remarkably relevant to insulin resistance index. We also found that the expression of Chemerin and its receptor was increased in granulosa cells of PCOS patients. Thus we hypothesized that Chemerin might decrease FSH sensitivity and insulin responsiveness, inhibit granulosa cell proliferation and induce apoptosis, finally contributing to the pathophysiology of PCOS. In this study, we will firstly use follicle fluid and primary granulosa cells to reveal the effect of Chemerin on FSH or insulin sensitivity and steroidogenesis in follicles. We will then adopt.immortalized human granulosa cell line KGN for in vitro studies to investigate the regulation of granulosa cell proliferation and apoptosis by Chemerin and its receptor. We would like to explore the underlying mechanisms. This study is innovative and it might provide new insights and proof for the prognosis and treatment of PCOS.

多囊卵巢综合征（PCOS）是育龄期妇女常见的内分泌和代谢紊乱疾病，以持续不排卵、雄激素过多和胰岛素抵抗为主要临床特征。研究表明PCOS患者中卵巢局部糖代谢异常，且卵巢颗粒细胞对FSH敏感性降低，增殖减少凋亡增加。我们前期研究发现在PCOS患者中，脂肪因子Chemerin血清水平显著升高且与胰岛素抵抗指数呈显著正相关； Chemerin及受体在卵巢颗粒细胞中的表达增加。由此我们推测Chemerin可能通过降低颗粒细胞对FSH和胰岛素的敏感性，抑制颗粒细胞增殖，促进其凋亡，参与PCOS的发展。本研究采用卵泡液和颗粒细胞为对象，分析Chemerin对FSH和胰岛素的敏感性和对激素合成的影响；利用人卵巢颗粒细胞系KGN进行体外实验，明确Chemerin及受体对颗粒细胞增殖及凋亡的调控，探讨其可能的作用机制。本研究具有创新性，可为PCOS早期防治提供新思路和科学证据，具有重要的理论意义和临床价值。

多囊卵巢综合征（PCOS）是育龄期妇女常见的内分泌疾病，以排卵障碍、雄激素过多为主要临床特征，且患者多伴有胰岛素抵抗和肥胖等临床表现。PCOS 如何防治已成为一个亟需解决的世界性医学问题。我们知道雌、孕激素的合成和分泌依赖于卵泡的正常发育和排卵，而卵泡中卵巢颗粒细胞的增殖凋亡被认为在PCOS的形成中发挥重要作用。脂肪因子Chemerin主要由脂肪组织分泌，多个研究已发现血清Chemerin水平与肥胖相关。我们前期研究发现，PCOS患者血清Chemerin水平显著升高，而且与PCOS患者本身的糖脂代谢异常、胰岛素抵抗和慢性炎症有关；血清Chemerin水平能够指示卵泡液中Chemerin水平，可以用来评估卵巢局部的代谢状态。我们进一步发现，PCOS患者卵巢颗粒细胞中Chemerin及受体CMKLR1的表达显著升高；我们发现外源性Chemerin抑制了卵巢颗粒细胞雌、孕激素的合成与分泌，降低了FSH受体、胰岛素受体和芳香化酶的表达，抑制卵巢颗粒细胞的增殖，促进其凋亡；我们利用siRNA干扰技术降低受体CMKLR1的表达，发现CMKLR1的表达干扰逆转了Chemerin对卵巢颗粒细胞的作用。我们进一步发现，外源性Chemerin降低了卵巢颗粒细胞中cAMP的分泌以及PKA底物的磷酸化，同时降低了卵巢颗粒细胞中Akt的磷酸化；基于以上研究结果我们推测，Chemerin对于卵巢颗粒细胞激素合成以及增殖凋亡的调控作用可能是通过抑制FSHR/cAMP/PKA信号通路来降低卵巢颗粒细胞对于FSH的敏感性从而导致卵泡的发育障碍和闭锁，通过抑制IGF-1R/PI3K/Akt信号通路来降低卵巢颗粒细胞对于胰岛素的敏感性从而导致卵巢的糖代谢受损。本项目研究结果提示Chemerin可能参与调控卵泡的生长发育与功能；血清Chemerin水平可能是PCOS患者发展成代谢综合征的早期标志物。研究结果同时提示Chemerin对卵巢颗粒细胞的调节作用依赖于受体CMKLR1，靶向降低chemerin受体CMKLR1的表达可能是治疗多囊卵巢综合征糖脂代谢异常和内分泌异常的新途径。本研究为PCOS发生发展的机制研究提供新思路，具有潜在的重要的经济价值和社会价值。