线粒体氧化损伤介导的细胞凋亡和自噬在母体低硒致胎盘形态功能异常中的作用及机制研究

Selenium is an essential trace element for human and animal growth and development. Selenoprotein plays an important role in anti-oxidation, anti-inflammation and detoxification. In today's world, selenium deficiency is an increasingly prominent nutritional problem. Recent studies have shown that pregnancy-related diseases such as preeclampsia, intrauterine growth restriction and abortion are associated with maternal selenium deficiency. However, the current research on maternal selenium deficiency and pregnancy-related diseases is only at the level of correlation analysis, and reliable basic research has rarely been reported. Previously, we have confirmed that maternal selenium deficiency increases the level of oxidative stress in placenta, decreases the ability of proliferation, invasion, hormone synthesis and induces apoptosis of trophoblast cells, but the specific mechanism has not yet been clarified. Therefore, we speculate that "selenium deficiency in female mice may cause mitochondrial oxidative damage, inhibit the protective role of autophagy, trigger apoptosis and change placental morphology and function by reducing the antioxidant activity of selenoproteins, raising the level of oxidative stress". In this study, we intend to clarify the damage of placental structure and function caused by selenium deficiency in maternal placenta through the two levels, which are selenium-deficient placenta and trophoblast cells low-expressed of selenoproteins, and to further study the mechanism of mitochondrial oxidative damage, the effect of selenium deficiency on autophagy, and the interaction between autophagy and apoptosis in selenium deficiency. This study can open up a new way for finding the pathogenic factors of pregnancy-related diseases, and provide a new choice for the prevention and treatment of pregnancy-related diseases.

硒是人和动物生长发育的必需微量元素，以硒蛋白为主要形式发挥抗氧化作用。硒缺乏是当今世界日益凸显的营养性问题。近期研究显示，先兆子痫、宫内生长受限、流产等妊娠相关疾病与母体低硒存在关联性。然而，目前关于母体低硒与妊娠相关疾病的研究仅停留在相关性分析层面，可靠的基础研究鲜有报道。前期我们已证实，母体低硒使胎盘氧化应激水平升高，增殖、侵袭、激素合成能力减弱，滋养层细胞凋亡，但具体机制尚未阐明。据此，我们推测“母体低硒可能通过降低硒蛋白抗氧化活性，抬高氧化应激水平，引起线粒体氧化损伤，抑制自噬的保护作用，触发凋亡，改变胎盘形态功能”。本课题拟通过低硒胎盘和硒蛋白低表达滋养层细胞两个层面，明确母体低硒导致胎盘结构功能损伤的作用，并深入研究线粒体氧化损伤机制、硒缺乏对自噬的影响及自噬与凋亡在硒缺乏时的相互作用关系。本研究可为寻找妊娠期相关疾病的发病因素开辟新思路，为妊娠期相关疾病的防治提供新选择。

硒作为一种人和动物必需的微量元素，主要以硒蛋白形式发挥抗氧化作用。研究显示，妊娠相关疾病的发生与母体低硒呈负相关，但可靠的基础研究鲜有报道。胎盘作为母胎间联系的重要器官，对维持正常妊娠过程十分重要。母体低硒是否通过影响胎盘的结构、功能进而影响妊娠的结局，是我们需要探讨的问题。因此，本项目从动物层面明确了母鼠低硒使胎盘氧化应激水平升高，抑制胎盘滋养层细胞增殖，诱发胎盘滋养层细胞自噬过程且阻滞自噬流，引起细胞凋亡的现象。转录组测序揭示了母鼠低硒不仅会抑制胎盘的物质转运和激素合成功能，还会促进胎盘中的免疫反应。通过构建体外硒蛋白低表达滋养层细胞模型明确了硒蛋白低表达抬高滋养层细胞氧化应激水平，抑制其增殖、激素合成和侵袭能力；阐明了硒蛋白低表达通过氧化应激介导自噬，但抑制保护性自噬，进而触发凋亡的分子机制。上游AKT/mTOR信号通路参与硒蛋白低表达对滋养层细胞功能的改变。本研究为寻找妊娠期相关疾病的发病因素开辟新思路。