Nrf2通过circ-Vps41/miR-26a-5p/CaMKIV调控网络改善衰老相关学习记忆障碍的机制研究

人口老龄化伴随的衰老相关学习记忆障碍是世界各国面临的重要卫生问题。目前研究认为氧化应激是其发生发展的核心环节。抗氧化应激相关转录因子Nrf2的适应性表达能力随年龄的增长而降低，并引起小鼠海马脑区神经元突触可塑性破坏，继而导致学习记忆能力下降。课题组结合前期发现，通过全转录组基因芯片检测了野生型与Nrf2-/-小鼠海马脑区中的circRNA和mRNA表达谱，基于生信分析结果提出Nrf2参与调控衰老相关学习记忆障碍及突触可塑性的表观遗传学机制。本项目拟首先明确Nrf2上调circ-Vps41表达的分子机制，并探索circ-Vps41作为竞争性内源RNA的circ-Vps41/miR-26a-5p/CaMKIV调控网络，最终阐明Nrf2是否通过该调控网络改善衰老相关学习记忆障碍和突触可塑性破坏，以期获得Nrf2调控衰老相关学习记忆障碍的新机制，为相关生物标志物和干预靶点的开发提供新思路。

The aging-related learning and memory impairments associated with aging are important health issues facing countries around the world. Current research believes that oxidative stress is the core reason. And the anti-oxidative stress-related transcription factor, Nrf2, which is decreased with age, causes the destruction of synaptic plasticity in hippocampus of mice, which in turn leads to a decline in learning and memory. Based on the previous findings, our research team detected the expression profiles of circRNA and mRNA in the hippocampus from wild-type mice and Nrf2-/- mice by whole transcriptome gene chip technology. The results show that Nrf2 regulates aging-related learning and memory disorders and synaptic plasticity through its epigenetic regulatory mechanism. This project firstly intends to detect the binding site of Nrf2 and the promoter of Vps41 gene to clarify the molecular mechanism of Nrf2 up-regulation of circ-Vps41 expression. Then, the project tends to research the regulatory network of circ-Vps41, which serve as miR-26a-5p sponge to regulate CaMKIV mRNA. Finally, the role of the network in aging-related learning and memory disorders and synaptic plasticity destruction will be verified. All in all, we are looking forward to finding a new mechanism of Nrf2, and finding new biomarkers and effective intervention targets for improving age-related learning and memory disorders.