高迁移率族蛋白B1（HMGB1）参与多种疾病的发生,以其为靶点探索相关干预策略受到高度关注。HMGB1在生殖生理和生殖病理中的作用尚不清楚。本项目的前期数据显示，HMGB1的表达与子宫内膜基质细胞的蜕膜化相关，其表达异常可能导致反复流产的发生;抑制HMGB1活性或敲低其表达能显著改变线粒体的质量控制指标并抑制体内外蜕膜化进程。基于前期研究基础，本研究拟利用反复流产病例、HMGB1子宫条件性敲除小鼠和体外模型，1）探索HMGB1通过结合ER/PR对其应答基因转录和对蜕膜化过程的影响；2）激活AKT/STAT1信号通路对HMGB1乙酰化的诱导并促其核-浆转位的机制；3）胞浆HMGB1通过RAGE或其它受体调控线粒体的质量控制对蜕膜化进程的影响以及与反复流产发生的相关性，从而阐明本研究提出的“HMGB1通过核-浆双途径调控子宫内膜蜕膜化”的机制假说。成果有望为反复流产的诊治提供借鉴。

High mobility group protein B1 (HMGB1) is involved in the development of a variety of diseases. The studies of therapeutic strategies targeting this protein have been highly concerned. However, the role and regulatory mechanism of HMGB1 in female reproductive physiology and pathology are still uncovered. Our preliminary data in vitro and in vivo, have shown that HMGB1 is able to regulate decidualization and HMGB1 may be involved in the occurrence of recurrent abortion. HMGB1 knock-down by siRNA or inhibition of its activity by chemical reagents can significantly alter mitochondrial quality control factors and lead to compromised decidualization. Based on the results of previous experiments, this study will take advantages of URM cases, HMGB1 uterine conditional knockout mice and in vitro models to explore: the regulatory mechanism by which HMGB1, in combination with ER / PR, induces response genes transcription to influence decidualization; how the AKT/STAT1 signaling pathway activation induces acetylation of the nuclear localization domain in HMGB1 which could accelerate its nuclear-plasma translocation; how cytoplasmic HMGB1 affects the process of decidualization through the control of mitochondrial mass by RAGE or other receptors, and how this abnormal regulation correlates with the occurrence of unexplained recurrent miscarriage. Results of such investigations will help in elucidating the hypothesized mechanism that HMGB1 regulates decidualization through the nucleus-plasma dual pathway. The findings of this project are expected to explain the potential causes of recurrent miscarriage.