HDAC6介导的Prx2乙酰化修饰在脑梗死后神经元凋亡中的作用

脑梗死具有发病率高、致残率高和死亡率高等特点，亟需探寻有效防治措施。我们前期研究发现与野生型小鼠相比，组蛋白去乙酰化酶（histone deacetylase, HDAC）6基因敲除小鼠脑梗死后梗死体积明显变小，神经功能损伤明显变轻，梗死周边脑组织神经元凋亡明显变少，但造成以上表型变化的具体机制目前尚不清楚。. 过氧化物还原酶（peroxiredoxin, Prx）2可以通过氧化还原反应降低氧化应激引起的细胞凋亡，乙酰化修饰的Prx2蛋白其抗氧化应激能力明显提高。前期研究发现HDAC6能够降低Prx2的乙酰化修饰水平。因此，我们提出假设：HDAC6通过降低Prx2乙酰化修饰而加重脑梗死后神经功能损伤。本项目拟应用基因工程小鼠，以脑梗死后相关表型为切入点，从整体、细胞、分子和基因水平阐明HDAC6在脑梗死发生发展中的作用及其机制。研究结果将为脑梗死后神经元保护治疗提供新靶点。

Stroke is the third leading cause of morbidity and mortality worldwide. Therefore, development of effective therapies for stroke patients is crucial. Our previous data suggested that histone deacetylase 6(HDAC6) gene knockout mouse showed significantly reduced lesion volume, decreased functional impairments and neuron apoptosis when compared to wide type mouse after stroke. The mechanisms by which HDAC6 knockout mouse exhibited reduced lesion volume, functional impairments and neuron apoptosis after stroke remain unclear...Peroxiredoxin(Prx) 2 exerts a protective role in oxidative stress-induced neuronal cell death. The anti-oxidant effects of Prx2 are significantly enhanced when Prx2 is acetylated modification. Our previous data indicated that HDAC6 can target Prx2 and reduce the acetylated level of Prx2. Based on the above data, we made the assumption that the functional impairments and neuronal apoptosis after stroke may be attributed to reduced acetylated level of Prx2 which is regulated by HDAC6. So we chose to focus on this pathway for our investigation, and we intend to clarify the possible mechanisms by which HDAC6 deficiency reduces lesion volume, functional impairments and neuronal apoptosis after stroke. This study may offer a novel target for effectively neuroprotective treatments after stroke.