Fgf2在子痫前期引起的胚胎神经元发生缺陷中的作用及调控机制研究

Preeclampsia occurs after approximately 20 weeks in pregnancy, which matches with the critical stage for fetal brain development in utero. However, the developmental changes and underlying mechanisms in fetal brain in preeclampsia are largely unknown. Our previous study has shown deficiencies in neurogenesis and ability of spatial learning& memory in the postnatal offspring from preeclampsia-like rats, and neurogenesis-related gene Fgf2 is hypo-expression compared to control in brain. We hypothesize that the histone acetylation of Fgf2 gene in regulatory regions is changed under deleterious environment in utero, causing hypo-expression of Fgf2 which impaired embryonic neurogenesis at critical time-point. This project contains three parts: 1) to find the critical time-point for nonreversible impairment of embryonic neurogenesis in fetus from preeclampsia. 2) to find the expression pattern of Fgf2 at critical time-point and role of Fgf2 gene in the pathogenesis. 3) to find the relationship among histone acetylation, expression of Fgf2 and neurogenesis in preeclampsia. Overall, the project may provide a new insight on the pathogenesis of developmental changes in fetal brain from preeclampsia which may aid in the development of therapeutic approaches.

子痫前期发病期与胚胎神经元发生的关键期一致，但其对胚胎期子代神经元发生的影响及机制不明。我们前期研究发现子痫前期子代在出生后仍存在神经元发生缺陷及学习记忆障碍，并且大脑Fgf2的表达低于正常组。本项目在前期工作基础上提出假设：子痫前期造成的宫内不良环境在“关键时间点”通过改变Fgf2基因表达调控相关位点的组蛋白乙酰化水平，从而导致Fgf2的持续性低表达进而引起子代胚胎期神经元发生缺陷。研究内容：首先，研究子痫前期对胚胎期子代神经元发生的影响，并确定不可逆神经元发生缺陷的“关键时间点”；其次，分析“关键时间点”Fgf2对子痫前期胚胎期子代神经元发生的影响；最后，分析“关键时间点”Fgf2基因表达调控相关位点的组蛋白乙酰化水平对子痫前期胚胎期子代神经元发生的影响。本项目为子痫前期对子代神经系统发育的影响及机制提供新的思路，为改善子痫前期子代大脑发育及功能提供理论依据和分子靶点。