线粒体代谢及神经细胞损伤在低氧诱导的高级脑功能障碍中的作用及机制

The hypoxia environment in Tibet Plateau, which has a large number of immigrates population, has posed a potential threat on the health of local pregnant and newborn population and brought a major public issue. Previous study showed that prenatal hypoxia exposure cast a significantly negative effect on the development and advanced function of neural system in newborn population. Our research also reported that prenatal hypoxia exposure led to cognitive dysfunction by reduction of neural stem cells and neurons, increasing the ratio of necrotic cells, and inducing mitochondrial metabolic dysfunction. These clues suggested that hypoxia-induced brain dysfunction is closely related to mitochondrial metabolic dysfunction and neural cell damage. The hypoxia-induced mitochondrial metabolic dysfunction occurs as the following process: compensatory decompensated - disorder - cell death. However, the detailed mechanisms of hypoxia-induced mitochondrial metabolic dysfunction and injuries in advanced brain functions remain unknown. Thus in this project, in vivo and in vitro models and epidemiological methods will be utilized to measure the effects of prenatal hypoxia exposure on the advanced brain function of the offspring, and the vital role of mitochondrial metabolic dysfunction in hypoxia-induced neural cell damage will be revealed. Furthermore, the detailed mechanisms of cold inducible RNA binding protein (CIRBP), which is a key protein in mitochondrial metabolic dysfunction mediated by HIF1a, will be elucidated. As a whole, our work will provide a potential target for the prevention and treatment of the prenatal hypoxia induced brain injury and establish a foundation for further clinical research of hypoxia protection.

青藏高原面积广阔，人口众多，低氧环境对孕产妇及新生儿的危害是不容忽视的重大公共卫生问题。既往研究表明，孕期低氧暴露对婴幼儿高级脑功能产生不利影响。我们前期研究也发现，孕期低氧暴露可使胎鼠神经干细胞和神经元数量降低，坏死细胞增加，线粒体代谢功能异常，新生鼠学习记忆功能降低，提示低氧引起的高级脑功能障碍可能与线粒体代谢和神经细胞损伤有关。在长期低氧暴露下线粒体代谢功能经历“代偿-失代偿-紊乱-细胞死亡”过程，低氧暴露下线粒体代谢功能的变化在神经细胞乃至高级神经功能损伤中的作用及机制尚待阐明。因此本项目拟应用流行病学研究及孕期低氧暴露模型，观察孕期低氧暴露对新生儿高级脑功能的影响，阐明线粒体代谢功能异常在神经细胞损伤中的核心作用，揭示CIRBP转录后调节HIF1a相关分子在低氧诱导线粒体代谢改变中的关键机制，为低氧诱导高级脑功能损伤的防治提供有效靶点，为实现生命早期低氧保护提供重要科学参考。

我国高原面积广阔，孕产妇和新生儿数量随着移居人口的增多逐年增加。然而低氧环境对孕产妇及新生儿的危害仍无有效的防护策略。. 本课题通过建立的西藏拉萨地区和陕西西安两地孕期低氧暴露的新生儿前瞻性队列。在新生儿出生后6个月、12个月、18个月对其进行随访，利用ASQ-3量表、ASQ-SE2量表进行综合性发育筛查与社会-情绪能力评估，并利用贝利婴幼儿发展量表进行神经发育水平评估。发现了高原低氧暴露可增加婴幼儿神经发育的异常风险。.以孕期低氧暴露的小鼠模型为基础，监测了孕期低氧暴露子鼠的一般生理指标：受孕率、胎鼠死亡率、身长、体重以及大脑半球的发育情况等。对孕期不同时间点的大脑皮层神经元数量和神经前体细胞的增殖、分化能力进行了检测与分析，初步揭示了孕期低氧暴露能够引起小鼠中间前体细胞数目减少，神经前体细胞增殖能力增强但其分化能力减弱的现象；明确了低氧暴露能够通过调控Drp1及MFN2的表达调控线粒体融合分裂，诱导神经干细胞发育异常，引起神经前体细胞增殖能力减弱；阐明了CIRBP介导的CCK8、Dpysl2改变在孕期低氧暴露神经前体细胞线粒体形态功能异常中的作用及分子机制。. 通过对出生后小鼠低氧暴露模型的研究，发现了低氧暴露能降低海马成熟神经元数量、抑制海马神经元突触功能。揭示了线粒体功能障碍在低氧暴露诱导神经元功能异常中的重要作用。发现了CIRBP分子在孕期低氧暴露中的改变规律，并阐明了CIRBP在孕期低氧暴露诱导神经元成熟障碍及脑功能损伤中的作用及机制。同时发现了孕期低氧暴露能够诱导神经元铁死亡的发生。通过添加外源性铁死亡抑制剂Fer-1可以部分缓解原代神经元的存活率下降，阐明了铁死亡在低氧暴露诱导神经元死亡中的作用及机制。. 本课题基于以上的研究初步揭示了生命早期高原低氧暴露对高级脑功能的影响；发现了低氧暴露下的神经细胞损伤与线粒体代谢的关系，阐明了CIRBP在低氧暴露诱导神经细胞损伤中的调节机制，为特殊环境高级脑功能的防治研究指明了新靶点。