近年来的研究发现精子对胚胎的发育具有十分关键的作用，其中表观遗传修饰在精子的跨代遗传中扮演重要角色。目前，由精子组蛋白修饰与DNA甲基化改变所引起的表观遗传异常已越来越受到关注。我们前期发现一个负责组蛋白泛素化连接酶HUWE1参与移植前胚胎发育。本研究拟利用前期建立的受精卵基因敲减模型及睾丸生精细胞特异的条件性敲除小鼠模型，研究HUWE1对胎盘及胚胎发育的影响及机制，并对筛选出的针对HUWE1的抑制剂进行体外细胞学实验验证，同时通过临床研究对精子HUWE1的表达与氧化应激，DNA损伤及流产的临床指标的相关性进行多因素分析。我们的结果将为明确HUWE1通过精子的组蛋白修饰传递对后代发育影响的具体机制提供科学依据, 同时将有助于阐明与辅助生殖有关的不明原因流产的病因。

Recent studies have shown that sperm play critical roles in embryo development and epigenetic modification of sperm is critically involved in transgenerational inheritance. Sperm histone modification and DNA methylation abnormality as the two major epigenetic abnormalities have drawn much attention. Our previous study has shown that HUWE1, a histone ubiquitin ligase, plays important role in preimplantation embryo development. In the current project, we plan to establish a zygotes Huwe1 knock-down model, a spermatocyte specific Huwe1 conditional knockout model and investigate the effect of HUWE1 gene on the placenta and embryo development and the underlying mechanisms. Furthermore, we aim to confirm the function of potential inhibitor of HUWE1 in the cell model and finally, we would like to explore the relationship between the expression of HUWE1 in sperm with parameters of oxidative stress and DNA damage. Our results will provide scientific evidence of the sperm HUWE1- mediated histone modification to affect embryo development as well as the mechanistic insight of IVF related miscarriage in clinic.