弥漫性白质损伤是脑小血管病的重要病理学特征，但发病机制目前尚不清楚，缺乏特异有效的治疗药物。NE是一种广泛存在于中性粒细胞和单核细胞内的蛋白酶，在病原体清除和组织细胞损伤中发挥重要作用。我们前期研究发现，以白质损伤为特点的脑小血管病模型中，脑组织内NE酶活性和NE蛋白表达均显著升高，并且NE可以促进原代少突胶质祖细胞凋亡、诱导DNA损伤修复基因Gadd45γ高表达。本项目拟通过小鼠双侧颈总动脉狭窄模型及原代细胞共培养，给予NE或NE特异性抑制剂，以及机制探讨时使用Gadd45γ–/–小鼠来源少突胶质细胞，研究：①脑小血管病不同损伤程度脑组织中NE的时空表达；②体内注射NE或NE特异性抑制剂，研究NE对髓鞘损伤的调控作用；③体外探究NE对原代少突胶质细胞分化和存活的影响，阐释NE通过Gadd45γ调控髓鞘损伤的机制。本项目将为脑小血管病机制研究提供新思路、新视角，为其治疗提供新靶标和新策略。

Diffuse white matter lesions are important pathological features in small vessel disease, but the pathogenesis is still unclear, and there is a lack of specific and effective therapeutic drugs. NE is a protease widely found in neutrophils and monocytes, which plays an important role in pathogen clearance and tissue injury. In our previous experiments, we found that the NE activity and NE protein expression in brain tissue was increased in mice with white matter injury. Furthermore, NE can induce primary oligodendrocytes apoptosis and Gadd45γ expression. In this project, we intend to detect the expression of NE in brain tissue with different degrees of white matter injury in mouse model of cerebral small vessel disease; NE or NE-specific inhibitors was used to study the effect of NE on oligodendrocytes in vivo and in vitro. Mechanistically, Gadd45γ–/–-derived oligodendrocytes were used to investigate whether NE affects oligodendrocyte differentiation and survival through Gadd45γ. It is expected to provide a new idea for the pathogenesis of white matter injury and a new target for the effective intervention in cerebral small vessel disease.