宫内高Leptin环境在子代的印记效应及其对子代学习记忆能力的影响及机制

"Adult disease, fetal traceability" opened up a new perspective of understanding disease. Gestational diabetes mellitus (GDM) progeny exist learning and memory capacity obstacles, which may related to disordered intrauterine environment. Leptin plays an important role in the development of hippocampus in early life, and can promote the hippocampus development and synaptic plasticity. We have found that the fetus of GDM mother developed in an intrauterine environment of abnormally elevated leptin, and its hippocampus leptin receptor expression was downregulated, what's more, its serum leptin level underwent a sudden decline after birth because of the withdrawal of placenta-derived leptin. It 's known that leptin and ObRb (leptin receptor)gene DNA were subject to methylation. We therefore have the hypothesis: in order to adapt to the higher leptin environment, the fetus (embryos) of GDM mother may change its methylation modality and lead to the downregulation of leptin and ObRb expression in hippocampus, and after birth there exist a "leptin withdrawal" period that the hippocampus is still in its key stage of development , which might affect the synaptic plasticity, and thus damage the neurocognitive ability of GDM offspring. On the basis of established GDM rat model, this project is to determine the leptin and ObRb gene promoter methylation level and the DNMT expression in hippocampus. Observe the synapse formation process, structure and function changes following leptin and ObRb expression changes. Explore the genetic imprinting effect of intrauterine high leptin environment and its impact on cognitive ability of GDM offspring. And eventually provid the theory basis for disease control at its source.

"成年疾病,胎儿溯源"开辟了认识疾病的新视角。妊娠期糖尿病（GDM）子代学习记忆能力存在障碍，可能与宫内不良环境相关。瘦素在生命早期海马发育中起着重要作用，能促进海马突触发育及可塑性。我们研究发现，GDM胎儿处于母体异常升高的瘦素环境中发育，其海马瘦素受体表达下调，而子代出生后胎盘源性瘦素突然中断。已知瘦素及其受体基因易于受到甲基化修饰，我们推测：胚胎为适应高瘦素环境可能改变甲基化修饰模式，导致子代海马瘦素受体表达下调，而出生后又存在"瘦素戒断"，使处于发育关键期的海马突触发育和可塑性受到影响，从而损害子代认知功能。本项目在已建立GDM大鼠模型的基础上，拟检测GDM子鼠海马瘦素及其受体基因启动子甲基化程度及DNMT表达水平；观察瘦素及其受体表达改变对子代突触形成过程、结构和功能的影响。探讨宫内高瘦素环境致子代基因印迹在海马突触发育及可塑性的调控作用及分子途径。为实现疾病源头控制提供理论依据