GluR6介导的凋亡机制在帕金森病发病中的作用研究

黑质多巴胺(DA)神经元进行性死亡是PD 发病原因。我们前期试验表明JNK 信号通路的过度激活是DA 神经元凋亡重要原因之一。JNK的激活受多种因素调控，近来研究显示谷氨酸受体(GluR)参与DA 神经元死亡。本项目提出有别于经典兴奋性毒性、钙超载理论新机制--海人藻酸受体（KAR）亚型GluR6 激活参与DA神经元死亡。借助研究信号模块中蛋白质-蛋白质的相互作用、蛋白活化对这种作用的调节及效应分子的激活等手段，探讨GluR6oPSD-95oMLK3 信号模块组装机制以及对JNK 信号通路介导的DA 神经元凋亡的作用。同时依据前期基金成熟技术，设计小肽Tat-GluR6-C，期望干扰GluR6oPSD-95oMLK3 信号模块组装，从而抑制JNK 通路的异常激活，最终揭示帕金森病中GluR6 介导JNK 激活，导致DA 神经元凋亡的分子机制，为探索 PD 治疗的新途径提供理论及实验依据。

Parkinson's Disease (PD) is the most common movement disorder. The progressive dopaminergic (DA) neuronal death in substantia nigra is the main pathogenetic character of PD. Our preliminary studies showed that the excessive activation of the JNK signaling pathway led to the apoptosis of DA neuron. Recent studies demostrated that glutamate receptors(GluR) are involved in the death of DA neuron.We propose that GluR6,one of KAR subtypes, may activate JNK pathway then cause DA neuron death. In order to study this, we will explore the GluR6 o PSD-95 o MLK3 signal module assembly mechanism and try to figure out if GluR6 may affect JNK activation and JNK downstream signaling pathways.We will investigate this signal template through protein - protein interactions, phosphorylation and effectors molecule activation et al. Based on the sequence of GluR6 binding domain of PSD-95, we will synthesize that the Tat-GluR6-C which could interfere the combination of GluR6 o PSD-95 o MLK3 and finally inhibit the activation of JNK signaling pathway.Our ultimate goal is reveal that GluR6 activation will lead to DA neurons death through JNK pathway.Our project will provide the useful theoretical and experimental information for the novel treatment of PD.