染色质重塑因子调控Th1/Th17细胞分化在早发性卵巢功能不全发生中的机制研究

Premature ovarian insufficiency (POI) is a clinical syndrome defined by loss of ovarian activity before the age of 40. It poses a serious threat to the health of women. The underlying explanation for POI remains to be elucidated in most cases; however, the role of cellular immunity in the pathogenesis of POI has gained increasing attention nowadays. The percentage of Th1 and Th17 cells and their cytokines were higher in the peripheral blood in patients with POI than those in controls. In the spleen of autoimmune ovarian disease mouse, the mRNA levels of T-bet and Rorc were up-regulated. Moreover, the mRNA level of BPTF in CD4+T cells of POI patients was decreased than that in healthy women. Interestingly, CD4+T cell-specific BPTF deletion led to increased Th1 and Th17 percentage in the periphery, and increased lymphocyte infiltration in the ovarian tissues. The results of our previous research suggested that BPTF regulating Th1 and Th17 cell function might play a role in the pathogenesis of POI. Based on the previous results, the present study aims to study the mechanism of how BPTF interacts with NRF2 to regulate Th1/Th17 differentiation and ovarian function, thus helping to provide new clues for the prevention, intervention and treatment of patients with POI.

早发性卵巢功能不全（premature ovarian insufficiency, POI）指40岁前卵巢功能衰退的临床综合征，严重危害女性生育力和健康。POI病因复杂，近年来细胞免疫在POI发病中的作用受到关注，但具体机制尚不明确。我们前期发现，POI患者外周血Th1、Th17细胞及其细胞因子较对照组升高；免疫性POI小鼠脾脏中Th1/Th17细胞相关转录因子表达增加。同时，染色质重塑因子BPTF（bromodomain PHD finger transcription factor）在POI患者CD4+T细胞中明显下调，且CD4+T细胞内特异性敲除BPTF基因小鼠的卵巢内有大量淋巴细胞浸润，提示BPTF可能通过调控Th1/Th17细胞参与POI的发生。本项目拟在前期基础上，探讨BPTF通过结合NRF2调节Th1/Th17细胞分化及卵巢功能的作用及机制，为POI的干预提供新思路。

早发性卵巢功能不全（POI）严重威胁育龄期女性健康。卵巢组织的纤维化是POI的一项病理特征。卵巢间质细胞在卵巢纤维化中发挥重要作用，但卵巢间质细胞对POI发生的微环境影响鲜有报道。而趋化因子在POI中的作用及可能机制尚未明确。本研究发现与正常对照女性相比，CXCL10在生化型POI患者及POI患者的血清中明显增加。同时，免疫性POI小鼠模型的血清中也发现了CXCL10水平的升高。血清中CXCL10水平与卵泡刺激素水平正相关，与窦卵泡数呈负相关。COL1A1 和 COL1A2 是I型胶原酶的两个亚型，本研究首次发现了CXCL10通过激活JNK/c-Jun信号通路，促进小鼠原代间质细胞的COL1A1 和 COL1A2合成。应用JNK的抑制剂SP600125及c-Jun的小干扰转染原代小鼠间质细胞，我们发现均可逆转CXCL10对COL1A1 与COL1A2的合成作用。然而，CXCL10对原代人卵巢颗粒细胞的雌孕激素合成、细胞增殖与凋亡无作用。本研究提示CXCL10可能是识别早期阶段POI的新指标，同时对CXCL10在卵巢纤维化中的作用有了新认识。.此外，我们还对多囊卵巢综合征（PCOS）合并卵巢储备功能下降（DOR）患者的内分泌及糖脂代谢做了分析。本研究共纳入自2015年至2019年在仁济医院妇科内分泌门诊就诊的1179位患者及70位健康女性。在健康对照组、单纯PCOS组及合并DOR组三组中比较内分泌及糖脂代谢的多项指标。卵巢储备功能下降在PCOS中的比例为20.8%。与合并DOR组比较，身体质量指数和腰臀比在单纯PCOS患者中明显上升。三组中的内分泌指标，如黄体生成素、促卵泡激素、雌二醇、睾酮及雄烯二酮均有显著性差异。单纯PCOS组的空腹血清胰岛素及HOMA-IR指数较合并DOR组增加。综上，内分泌及糖脂代谢指标在PCOS组及合并DOR组中均有明显差异。