Mex3C诱导突触后FOS表达调控能量平衡及其在神经管发生中的作用研究

Neural tube defects,NTDs is a group common and extremely serious birth defects because of neural tube disclose or dysraphism, Energy metabolism abnormality such as obesity is one high risk factor of NTDs. But how energy balance regulatory involved in the development of neural tube is unknown.Our preliminary data show that Mex3c mutant mice have increased energy expenditure and are resistant to diet-induced obesity. Mex3c variants enhance fos mRNA nuclear export, stability and translation; Some research show Lepr is regulated by fos. We hypothesize that fos induction may play an important role in mediating the full signaling of signals regulating energy balance and one mechanism for Mex3c being involved in energy balance is regulating transsynaptic fos expression. And fos regulating Lepr involve the development of neural tube. We will explicit the relationship between Mex3c and transsynaptic fos expression through in vitro and Mex3c mutant mice. And In order to probe that the relationship between regulatory of energy balance and neural tube development, We will research the developmental status and the role of fos, Lepr in neural tube. So we can know the the role of energy balance in developmental neural tube and can define our next research directions of early diagnosis and intervene of neural tube defects.

神经管畸形(neural tube defects，NTDs)是一组神经管不闭合或闭合不全的严重出生缺陷，能量代谢异常是导致神经管畸形的高危因素，能量平衡参与神经管发生的调控机制尚不明确。本课题组前期研究发现Mex3c蛋白在胚胎神经管组织不均匀表达，Mex3c突变小鼠表现为显著的负能量平衡，Mex3c蛋白变种均可增强fos mRNA的核输出、稳定性。有研究发现NTDs相关的瘦素受体（Lepr）可能由fos调控。由此，我们推测Mex3c通过诱导突触后fos表达调节能量平衡；fos通过调控Lepr表达参与神经管发生。本研究拟通过体外及Mex3c突变小鼠体内实验明确Mex3c与突触后fos表达的关系，并通过对正负能量代谢状态下神经管发育及fos、Lepr作用研究，初步探讨能量平衡调控与神经管发育之间的关系，为了解能量平衡在神经管畸形发生中的作用，并探寻神经管畸形早期诊断及干预新途径提供理论依据。

神经管畸形(neural tube defects，NTDs)是一组神经管不闭合或闭合不全的严重出生缺陷，能量代谢异常是导致神经管畸形的高危因素，能量平衡参与神经管发生的调控机制尚不明确。本课题组前期研究发现Mex3c蛋白在胚胎神经管组织不均匀表达，Mex3c突变小鼠表现为显著的负能量平衡，Mex3c蛋白变种均可增强fos mRNA的核输出、稳定性。有研究发现NTDs相关的瘦素受体（Lepr）可能由fos调控。由此，我们推测Mex3c通过诱导突触后fos表达调节能量平衡；fos通过调控Lepr表达参与神经管发生。本研究拟通过体外及Mex3c突变小鼠体内实验明确Mex3c与突触后fos表达的关系，并通过对正负能量代谢状态下神经管发育及fos、Lepr作用研究，初步探讨能量平衡调控与神经管发育之间的关系，为了解能量平衡在神经管畸形发生中的作用，并探寻神经管畸形早期诊断及干预新途径提供理论依据。.细胞实验中我们发现在体外培养的人神经母细胞瘤细胞SH-SY5Y中，感染具有组成性启动子控制Mex3C-1表达的pLV-CMV-Mex3C慢病毒构建稳定过表达细胞株，可以过量表达 Mex3C-1，对于卡巴胆碱Carbachol诱导的Fos表达，可以上调Fos表达强度，并延长其半衰期，增强Fos稳定性。 .动物实验中我们发现Mex3c通过诱导下丘脑c-fos的表达，参与了体内能量代谢过程。此外，能量平衡的失调使得雌性小鼠胚胎神经管在正常发育中出现缺陷。.本研究利用体外培养的细胞和转基因小鼠来研究Mex3c对突触后fos表达影响，并确定其是否是Mex3c参与能量平衡调控的机制，同时揭示了能量平衡在神经管发育中的作用。