DUSP6调控ERK/CREB通路介导神经干细胞分化在阿尔茨海默病中的作用

神经干细胞（NSCs）是治疗阿尔茨海默病（AD）的新策略，如何促进NSCs分化为神经元是目前研究的重点。我们在细胞模型中已证明：适当活化ERK可激活转录因子CREB促进NSCs向神经元分化；双特异性磷酸酶6（DUSP6）可靶向抑制 ERK过度磷酸化而保护NSCs。我们的单细胞测序结果显示AD小鼠模型的NSCs亚群中DUSP6显著下调，提示DUSP6 参与AD的NSCs分化调控，但DUSP6如何调控NSCs定向分化尚不清楚。我们假设：DUSP6可维持ERK适度活化，进而磷酸化激活CREB，从而促进NSCs定向分化。本项目拟采用DUSP6敲除小鼠及APP/PS1转基因小鼠，结合单细胞组学等新技术，阐明（1）DUSP6可调控ERK促进NSCs定向分化;（2）DUSP6促进NSCs分化的作用将由CREB介导。研究结果将为临床以NSCs治疗AD提供科学依据与新策略。

Neural stem cells (NSCs) therapy is a new strategy for the treatment of Alzheimer's disease (AD). It is crucial to promote the neuronal differentiation of NSCs. We have demonstrated that proper ERK activation can promote the neuronal differentiation of NSCs via CREB in vitro. Moreover, we have found that dual-specific phosphatase 6 (DUSP6) could selectively inhibit the hyperphosphorylation of ERK and protect NSCs. DUSP6 was significantly down-regulated in the NSCs subgroups of AD mouse models in the single-cell sequencing assay, suggesting that DUSP6 is involved in the regulation of NSCs differentiation. Nevertheless，the direct effect of DUSP6 on the regulation of the NSCs differentiation is still not fully understood. In our hypothesis, DUSP6 can maintain the proper activation of ERK, phosphorylate CREB, thereby promote the neuronal differentiation of NSCs. The DUSP6 knockout mice and APP/PS1 transgenic mice will be used in this project. New technologies such as single-cell omics will be selected to clarify if DUSP6 promotes the neuronal differentiation of NSCs through regulating ERK and CREB. The research will provide a scientific basis and new strategy for the clinical treatment of AD with NSCs.