p35/cdk5-DCX信号通路在砷暴露致未成熟脑损害中的作用研究

Arsenic exposure can affect the development of immature brain and neural network forming and the resulting dysfunction that continues throughout life, but the exact mechanism is still poorly understood. p35/cdk5 signaling pathways play a key role in important physiological and pathological process in the central nervous system. The pilot study found As2O3 exposure reduces the microtubule associated protein (DCX) expression which is p35/cdk5 signaling pathways downstream molecules, with relation to weakness of neuron migration, however, the exact mechanism remains to be further study. Therefore, we speculate that arsenic exposure through disturb the p35/cdk5-DCX signaling pathways and affecting the migration of cortex neurons and causing immature brain damage. In order to test this hypothesis, we used the established the primary cultured cortex neuron and As2O3 exposure model in infant rats, and Using the Nissl's staining, RT-qPCR, western blot, and water maze skills from the levels of gene, protein, tissue and animal to explore the function of p35/cdk5 - DCX signaling pathways in the arsenic exposure cause the immature brain damage. The results will help to understand the arsenic toxicity mechanism for neural development, and providing theoretical supporting for the prevention and control of arsenic exposure.

砷暴露可影响未成熟脑的发育和神经网络的构建并由此引起的功能异常可累及终生，但其.机制仍知之甚少。p35/cdk5信号通路在中枢神经系统的重要生理和病理过程中发挥重要作用。我们预实验发现As2O3暴露可通过减少p35/cdk5信号通路下游分子-微管相关蛋白（DCX）的表达降低乳鼠皮层神经元的迁移能力，但其具体机制有待进一步探讨。为此，我们推测：砷暴露可通过干扰p35/cdk5-DCX信号通路，影响未成熟脑皮层神经元的迁移，导致神经系统损害。为验证这一设想，我们利用已构建的大鼠皮层神经元原代细胞和幼鼠As2O3暴露模型，采用尼氏染色、RT-qPCR、western blot、水迷宫等手段，从基因、蛋白、组织以及动物整体水平等多方面探讨p35/cdk5-DCX信号通路在砷暴露致未成熟脑损害过程中发挥的作用。预期结果有助于阐明砷的神经发育毒性机制，并对砷暴露的综合防治提供理论依据。

发育关键期低浓度砷暴露对未成熟脑损害的机制仍不明确，不利于砷污染的防治。因此，研究砷暴露致未成熟脑损害的机制有其必要性和紧迫性。我们前期对As2O3对神经元迁移影响及其机制研究基础，在体外已经初步证实As2O3可干扰皮层神经的迁移，并初探其机制。本研究通过构建生后大脑快速发育期低浓度砷暴露模型，发现生后大脑快速发育期低浓度砷暴露可导致大鼠学习能力降低、焦虑行为增加、诱导出孤独症样行为，砷暴露组大鼠额叶皮层及海马短期内神经生发持续改变。从神经生发方面初步了解生后发育关键期低浓度砷暴露致病机制，为砷污染防治提供理论基础。