TOX3在多囊卵巢综合征卵泡发育异常中的作用及转化医学研究

As a highly complex disease with dysfunctions of endocrine and reproductive system, polycystic ovary syndrome (PCOS) affects 5.6%~8% of women of childbearing age. By genome-wide association study (GWAS) of more than ten thousand PCOS cases, our group found that TOX3 is a related gene of PCOS. In our previous studies, TOX3 was found highly expressed in hyperandrogenic or insulin resistant PCOS cases, as well as PCOS rat model, indicating TOX3 may play a crucial role in pathogenesis of PCOS. Adding androgen or insulin can stimulate expression of TOX3 in ovarian granulosa cells. However, the mechanism is still not clear and needs deep research. Therefore, this project is to study the function of TOX3 signaling pathway in follicle development, utilizing in vitro(high concentration of androgen/insulin stimulating cells, up/down regulation TOX3 gene) and in vivo(knockout/knockin Tox3 of granulosa cells in mouse models) research technique，and the relationship with PCOS. This study will illustrate the mechanism of abnormal TOX3 pathway in PCOS pathogenesis, and enrich fundamental reproductive biological theories.

多囊卵巢综合征（PCOS）是一个高度复杂的内分泌及生殖功能障碍性疾病，在育龄期妇女中约占5.6~8%，是造成不孕症的常见病因之一。课题组通过全基因组关联分析发现，TOX3基因是PCOS的一个易感基因，并且在PCOS患者中高表达，揭示TOX3在PCOS发病中可能扮演重要作用。课题组最近研究发现，雄激素或胰岛素可刺激体外卵巢颗粒细胞TOX3的表达，在PCOS大鼠模型中TOX3也高表达，而它们在PCOS发病中的作用机制仍有待深入研究。因此，本课题拟采用体外（雄激素/胰岛素刺激卵泡、上调/下调TOX3等）和体内（TOX3基因敲除/敲入小鼠等）手段，结合不同亚型PCOS患者进行验证的策略，系统研究TOX3在PCOS患者卵泡发育中的具体作用机制。阐明TOX3信号通路异常对PCOS的致病机理，丰富生殖生物学的基础理论，为治疗雄激素/胰岛素代谢异常相关疾病提供理论依据。