WRN基因突变造成DNA修复障碍和基因组稳定性异常，可诱发包括大脑在内的早期衰老和进行性发展的神经退行性变。SIRT6促进神经元DNA损伤修复并调节葡萄糖代谢，是DNA损伤反应中重要的调节和适应因子，在大脑衰老和神经退行性变过程中发挥的作用和调控机制不明。我们前期利用携带WRN基因突变的iPSCs诱导分化为不同类型的神经元，发现WRN基因突变神经元对氧化性DNA损伤敏感性明显增高，SIRT6反应性表达上调。据此我们推测SIRT6参与WRN基因突变神经元的DNA损伤反应，可能在促进DNA修复同时打破神经元糖代谢稳态，改变神经元对氧化应激的适应能力，影响大脑衰老和神经退行性变的进程。本研究拟应用WRN基因突变的神经元、脑类器官及动物模型，在细胞、类组织器官和活体水平阐明SIRT6在不同条件下调节神经元DNA损伤修复和葡萄糖代谢的作用机制，为脑老化及神经退行性疾病的预防和治疗提供新的思路。

Werner's syndrome patients features accelerated aging and progressive neurodegeneration. WRN deficient cells are characterized by impaired DNA repair and genome instability. SIRT6 responses to DNA damage and modulate glucose metabolism. However, the exact function and regulation mechanism of SIRT6 in neurons is still unclear. Our previous data has proved that WRNmut-iPSCs derived neurons showed significant higher DNA damage sensitivity and increased SIRT6 protein level. Here we hypothesize that SIRT6 response to DNA damage and promote DNA damage repair triggered by WRN mutation, which may disturb glucose metabolism homostasis and may further affect stress adaption capacity of specific type neurons. In this project, we will use WRNmut-iPSCs derived neurons and brain organoids as well as animal models to study the mechanism of SIRT6 coordinating DNA damage repair and glucose metabolism in neurons with WRN gene mutation. Elucidation of SIRT6 regulation and function mechanism in neurons may yield new insight in brain aging and neurodegeneration.