基于CCM3基因调控的血管损伤作用探讨宫内铅暴露小鼠神经毒性机制及基因治疗对其干预作用

生命早期铅暴露引发生命后期出现的远期健康危害的问题亟待解决。铅引发的神经退行性疾病如AD是最严重的累积损伤效应。CCM3基因缺陷造成的血管新生异常及其在加速AD病变中的潜在危险说明CCM3基因是铅促使AD发病的关键起源性分子事件。而使用具有脑微血管内皮靶向性AAV2-BR1-CAG-CCM3载体修复CCM3基因缺陷从而缓解铅引发AD极具可探索性，但对于CCM3基因在铅暴露经血管损伤引发神经病变中作用机制还不明确。故本研究拟以CCM3基因对血管损伤的调控作用为切入点，构建血管内皮特异性CCM3基因敲除小鼠的宫内铅暴露模型及血管内皮细胞和神经元细胞联合培养体外模型，结合磷酸化蛋白质组学技术深入探讨发育关键阶段铅暴露经CCM3基因引发血管损伤在成年后造成AD的作用机制，确定AAV2-BR1-CAG-CCM3载体对此的治疗效果，为铅暴露造成的神经退行性疾病AD的精准预防和治疗提供新的靶点和思路。

It needs to be solved the long-term health hazards in later life caused by Lead exposure in early life. The damage of Lead to nervous system such AD is the most serious cumulative damage effect. There is the abnormal angiogenesis and the potential risk in accelerating AD caused by CCM3 gene defect, which indicate that CCM3 gene is a key and source molecular event in AD induced by Lead. It is very exploratory to apply AAV2-BR1-CAG-CCM3 vector with specific targeting of cerebral microvascular endothelial cells to repair the defects of CCM3 gene and alleviate Lead-induced AD. But the mechanism of CCM3 gene in neuropathy via vascular injury induced by Lead exposure is still unclear. Therefore, it is intended to take the regulatory effect of CCM3 gene on vascular injury as the starting point, construct the model of intrauterine Lead exposure and the model of vascular and nerve cell co-culture, and further explore the mechanism of vascular injury induced by CCM3 gene in the critical stage of development, and determine if AAV2-BR1 -CAG-CCM3 carrier is a new idea for the precise prevention and treatment of neurodegenerative disease AD caused by Lead exposure.