PI3K/Akt通路调控母体低硒的新生儿心脏电活动异常分子机制的研究

Selenium is an essential trace element in human body, exerts anti-oxidation, immune regulation, thyroid hormone metabolism, and other biological functions mainly in the form of selenoproteins. Low selenium can lead to the occurrence of Keshan disease, cancer and some other diseases. Latest reports suggested that maternal low selenium increased the incidence of sudden death of newborn, which is also observed in Keshan disease, but the underlying mechanism is still unknown. In both clinical and animal experiments, we observed that selenium deficiency females and their offsprings' electrocardiogram (ECG) changed abnormally and their antioxidant function reduced. Consequently, we intended to establish clinical samples, animal models and cell models, in this three levels, to study the regulating mechanism that how maternal low selenium result in myocardial injury, cardiac ion channels expression changes, calcium overload and the activation of PI3K/Akt pathway of offsprings. We would elucidate the mechanisms of the effect that maternal low selenium make on offsprings' myocardium and cadiac electrophysiology, and make the study time window shift forward, to provide experimental basis of theory significance for prevention and treatment of myocardial damage caused by low selenium, and to enhance people's awareness of the harm of selenium deficiency, improving people's physical quality.

硒是一种机体必需的微量元素，主要以硒蛋白形式发挥抗氧化和免疫调节、甲状腺素代谢等生物学功能。低硒可导致克山病、肿瘤等疾病的发生。最新文献报道，产妇低硒时新生儿猝死增加，在克山病也常观察到类似情况，但机制不详。我们在临床和动物实验均观察到，低硒产妇和母鼠及其新生后代均发生心电图异常改变和抗氧化功能降低。鉴此，我们拟在临床低硒产妇、低硒大鼠及其子鼠模型和硒蛋白低表达细胞模型3个层次开展对母体低硒导致子代心肌损伤、心肌离子通道表达、钙超载和激活P13K-Akt通路的调节分子机制的研究。探究低硒如何影响胎盘功能、如何将低硒的损伤信息传递给胎儿，低硒与心肌细胞钙超载以及心肌钙通道的表达调控机制的关系。阐明母体低硒对子代心肌损伤和心脏电生理影响的分子机制，将低硒引起心肌损伤的研究时间窗前移，为预防与治疗低硒导致的心肌损伤提供有理论意义的实验依据，加强国人对硒缺乏危害的认识，提高我国人民的身体素质。

硒（ Se）是一种微量元素，它可以作为硒代半胱氨酸掺入形成各种硒蛋白，硒蛋白在调节甲状腺激素代谢，抗氧化防御和免疫系统中发挥了至关重要的作用。低硒与许多疾病相关，尤其是心血管疾病。前期研究发现，产妇低硒时新生儿猝死增加，且在克山病也常观察到类似情况。我们在临床和动物实验均观察到，低硒产妇和母鼠及其新生后代均发生心电图异常改变和抗氧化功能降低。为了阐明母体低硒对子代心肌损伤和心脏电生理影响的分子机制，本课题采用低硒喂养及干扰慢病毒载体方法构建低硒动物模型及硒蛋白低表达细胞模型，利用HE染色和电镜技术、ELISA等方法检测组织及细胞功能。实验结果显示，低硒可导致产妇和母鼠体内氧化应激水平升高，抗氧化应激能力降低；低硒产妇和新生后代均发生心电图异常；母鼠胎盘组织结构改变；低硒抑制滋养层细胞增殖迁移能力，并减少胎盘中绒毛膜促性腺激素和孕激素的合成；低硒下调PDK-1及磷酸化Akt的表达。我们发现，低硒并不单纯通过影响PDK1的表达而对Akt的磷酸化产生影响，还可能存在其他影响因子有待探究。低硒对母体及子代心脏功能的影响可能与抗氧化应激能力、胎盘功能及PI3K/Akt通路基因表达的改变有关，有助于了解硒对母体低硒导致的子代心肌损伤的影响机制。