衰老小鼠线粒体促凋亡蛋白Omi/HtrA2表达增加在加重帕金森病中的作用及机制研究

随年龄增长出现的神经细胞凋亡加重了帕金森病（Parkinson’s Disease, PD）的发生发展，但机制不清。研究发现PD患者及动物模型中线粒体促凋亡蛋白Omi表达增加或活性增强; 我们原创性研究提示,衰老神经细胞Omi表达增加与细胞凋亡密切相关。但异常表达的Omi在衰老PD中的作用如何、表达增加的Omi是否可通过促神经细胞凋亡加重PD仍需进一步证实。本研究拟以细胞凋亡为切入点，在分别检测成年及衰老PD小鼠Omi表达、活性及定位改变的基础上，通过立体定位注射Omi腺病毒构建黑质特异性过表达Omi小鼠并建立PD模型，观察其细胞衰老、凋亡及行为学改变，证明Omi/HtrA2可通过促进神经细胞凋亡加重衰老小鼠帕金森病；其次从Omi降解线粒体抗凋亡蛋白HAX-1和结合胞浆抗凋亡蛋白XIAP，分析衰老PD小鼠Omi促神经细胞凋亡的两种机制，为Omi用作潜在治疗神经退行性疾病靶点提供实验依据。

The increased rate of neuronal apoptosis with aging exacerbates Parkinson Disease (PD).The autopsy of PD patients and PD animal experiments showed that either expression or activity of Omi was increased. Moreover, our original research found that the increased expression of Omi was associated with neuronal apoptosis, which suggested the pro-apoptotic function of Omi enhanced the PD injury in aging mice. Therefore, we will observe the expression and activity of Omi in the aging PD mice, and the specific overexpression Omi in substanitia nigra was used to observe whether Omi was involved on PD-induced neuronal apoptosis and injury. Meanwhile the mechanisms responsible for this age-related Omi in PD remain unclear. Then we will identify the mechanisms and contributions of the Omi-HAX-1 of Omi-XIAP pathway in exacerbated PD injury in aging mice. Based on the findings from our studies, we hope to identify the possible role and significance of increased Omi in the aging brain.