基于下丘脑Kiss1-GnRH神经网络研究电针干预早期生殖衰老的效应及表观遗传学机制

雌激素(E2)正反馈促GnRH神经元活化减少引起LH高峰分泌衰减是女性早期生殖衰老的标志性特征。课题组证实随增龄发生在下丘脑AVPV的组蛋白H3乙酰化异常致Kiss1基因表达降低导致Kiss1-GnRH神经网络功能改变是关键原因，并发现电针能促进早期生殖衰老大鼠AVPV神经细胞组蛋白H3乙酰化、上调Kiss1表达并改善LH分泌低下。染色质构象改变是E2正反馈调控Kiss1基因表达的重要环节，本项目拟采用CHIP、染色质构象捕获3C、高通量染色质构象捕获测序合并生物信息学分析等方法，研究差异染色质构象介导E2调控Kiss1表达衰减致早期生殖衰老发生的机制；并从染色质构象角度研究电针通过表观遗传学机制调控Kiss1表达干预Kiss1-GnRH神经网络增龄性变化，阐释电针改善早期生殖衰老特征性表型并延缓生殖轴老化的效应及机制，以期为拓展电针干预女性生殖衰老提供科学依据。

Early female reproductive aging is characterized by reduced gonadotropin-releasing hormone (GnRH) neuronal activation and attentuated luteinizing hormone (LH) surges under estradiol (E2) positive feedback condition. Our previous works have demonstrated that hypothalamic Kiss1 gene decline resulted from age-related alteration of histone H3 acetylation in the Kiss1-GnRH network is the key mechanism, our recent data showed that electroacupuncture (EA) promotes neuronal histone H3 acetylation in the anteroperiventricular periventricular nucleus (AVPV)、upregulates Kiss1 gene synthesis and increases LH secretion in female reproductive aging rats. New publication indicated that chromatin loop conformation is the critical point underlying Kiss1 gene expression under E2 positive feedback. Using CHIP, chromatin formation capture 3C/Hi-C and neuron calcium imaging, this study aims to investigate: (1) chromatin loop conformation dysfunction mediates Kiss1 gene repression in the AVPV in early female reproductive aging; (2) EA improves female reproductive aging phenotypes and benefits reproductive aging process, EA may epigenetically modulats Kiss1 gene expression to intervene Kiss1-GnRH network aging. This project will provide noval scientific evidences for treating female reproductive aging with EA.