甲状腺激素核受体α1调控生长激素基因转录在小鼠海马早期发育中的机制研究

甲状腺激素（TH）和生长激素（GH）在脑发育过程中均发挥重要作用, 严重影响人类的生长发育和神经认知功能。GH基因的启动子区有甲状腺激素核受体的反应元件，那么TH是否通过调控GH的基因转录在脑发育中发挥作用呢？目前国内外未见报道。本课题组前期实验结果显示：TRα1基因突变小鼠（TRα1-E403X）有明显的海马发育障碍，而且TRα1突变导致了小鼠外周血中GH水平下降、以及GH和其下游信号通路的分子表达下降。我们推测GH可能参与了TRα1-E403X 基因突变导致的海马发育障碍。因此本课题将在前期研究结果基础上，进一步探讨TRα1调控海马GH基因转录的分子机制及其在小鼠海马早期发育中的作用。本研究将从TRα1调控GH基因转录的角度，提出甲状腺激素影响海马发育的一个新的机制，也将为临床上RTHα患者脑功能障碍的治疗提供新的治疗方法。

Both thyroid hormone (TH) and growth hormone (GH) play important roles in brain development, which seriously affect human growth and cognitive function. It was reported that there were thyroid hormone receptor response elements in the promoter of GH gene. Whether TH plays a role in brain development by regulating GH gene transcription is uncertain. Our previous experiments showed that TRα1 mutation (TRα1-E403X) resulted in the significant impairments of both the development of hippocampus and the long-term enhancement. TRα1 mutation also decreased the levels of serum GH, as well as the expressions of GH and its downstream signaling pathways molecules, suggesting that abnormal growth hormone and its downstream signaling pathway would be involved in the hippocampal development dysfunction caused by TRα1-E403X. Therefore, based on these preliminary results, we aimed to further explore the molecular mechanism of TRα1 regulating GH gene transcription, as well as its role in hippocampal development in mice. If this hypothesis is confirmed, TRα1 regulating GH gene transcription may be a new mechanism of thyroid hormone effects on the hippocampal development. Our study will also provide a new treatment for the brain dysfunction in patients with RTHα in clinic.