CFTR参与颗粒细胞增殖和卵泡发育及其在PCOS病理机制中的作用

Polycystic ovarian syndrome (PCOS), manifested by polycystic ovary and ovulation defect due to abnormal follicle development, is one of the most common disorders that cause female infertility. However, its underlying pathological mechanism is elusive. CFTR is an anion channel conducting both Cl- and HCO3-, mutations of which cause Cystic Fibrosis (CF). It has been reported that CF women present symptoms similar to that of PCOS, such as cystic ovary and ovulation disorder. In our preliminary study, we have demonstrated that CFTR is expressed in ovarian granulosa cell, which is downregulated in PCOS patients; inhibition of CFTR inhibits FSH-stimulated signaling pathway and granulosa cell proliferation, suggesting a role of CFTR in granulosa cell proliferation and follicle development, defect in CFTR may underlie the abnormal follicle development in PCOS. In the proposed study, we aim to: 1. elucidate the involvement of CFTR in granulosa cell proliferation and the underlying mechanism in a primary granulosa cell culture model; 2. demonstrate the involvement of CFTR in follicle development in an in vitro follicle culture system; 3. confirm the importance of CFTR-dependent pathway in granulosa cell proliferation and follicle development by PCOS animal model and PCOS patient samples. The findings of the proposed study may shed new light onto the understanding of molecular mechanism underlying the pathogenesis of PCOS and provide grounds for the development of new treatment strategies for PCOS.

多囊卵巢综合征（PCOS）是导致女性不育的最常见疾病之一。卵泡发育异常导致的卵巢多囊性改变和排卵障碍是其重要的临床表现，而目前其病理机制仍不清晰。CFTR是一个转运Cl-和HCO3-的离子通道。CFTR突变的女性病人常出现与PCOS相似的卵巢多囊性改变和排卵障碍。我们前期的研究发现CFTR在卵巢颗粒细胞中表达，并且在PCOS病人中下调，抑制CFTR可以抑制FSH相关信号通路和细胞增殖，提示CFTR可能参与颗粒细胞增殖从而参与卵泡发育，其缺陷可能是导致PCOS卵泡发育异常的原因之一。本课题拟用原代颗粒细胞研究CFTR参与颗粒细胞增殖的分子机制和信号通路，用卵泡体外培养模型研究CFTR在卵泡发育中的作用，通过PCOS动物模型和病人颗粒细胞验证CFTR 在调节细胞增殖信号通路中的作用。本研究对于阐明PCOS的发病机制将会有重要的突破，对治疗新方法的研发有重要的指导意义。

多囊卵巢综合征（PCOS）是导致女性不育的最常见疾病之一。卵泡发育异常导致的卵巢多囊性改变和排卵障碍是其重要的临床表现。目前其病理机制并不清晰。CFTR是一个转运Cl-和HCO3-的离子通道，其突变导致囊性纤维化病变(CF)。CF女性出现与PCOS相似的卵巢囊性改变。我们前期的研究发现CFTR在卵巢颗粒细胞中表达，并且在PCOS病人中下调，抑制CFTR可以抑制FSH相关信号通路和雌激素生成。在本课题中，我们进一步探讨CFTR在PCOS卵泡发育异常中所起的作用以及其中的机制。我们发现，CFTR在大鼠PCOS模型的颗粒细胞中表达下调，并伴随着PCNA表达降低；敲减或抑制CFTR导致颗粒细胞增殖减慢。我们证明CFTR通过HCO3 (-)/sAC/PKA信号通路，影响ERK磷酸化和Cyclin D2的表达，从而调节基础和FSH刺激的颗粒细胞增殖。在大鼠PCOS模型中，这一信号通路也受到抑制，ERK磷酸化减少，CyclinD2表达降低。这些结果表明CFTR参与正常卵泡发育，其表达下调抑制颗粒细胞增殖，从而导致PCOS中卵泡发育的异常。本研究的发现有助于阐明卵泡发育的分子机制和PCOS的发病机制，对治疗PCOS的新方法研发有一定的指导意义。