腺苷肌酶驱动的P1嘌呤信号异常在致痫机制中的作用研究

项目名称： 腺苷肌酶驱动的P1嘌呤信号异常在致痫机制中的作用研究

项目编号： No.81201006

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 神经系统疾病、精神疾病

项目作者： 康慧聪

作者单位： 华中科技大学

项目金额： 24万元

中文摘要： 腺苷可抑制兴奋性递质的作用而终止癫痫发作,从而被称为天然的"内源性抗癫痫物质"。腺苷激酶（ADK）是腺苷代谢的主要调节酶，急性癫痫发作时脑内ADK表达急剧下调，腺苷浓度急剧增高，刺激P1嘌呤受体抑制癫痫发作；然而我们在前期工作中却发现慢性复发性癫痫大鼠脑内ADK及嘌呤受体的改变与急性发作时相反，推测这种反向变化是导致腺苷的作用由抗癫痫向致癫痫转变的原因，ADK驱动的腺苷浓度及P1嘌呤信号异常可能是重要的致痫机制。同时神经元的GABA信号通路是嘌呤信号的重要靶点，而ADK主要由胶质细胞表达，因此嘌呤信号通路衔接的神经元-胶质细胞对话可能是深层的致痫机制。本项目从在体及体外两方面入手，采用基因工程、电生理、阻滞剂/激动剂等核心技术，对ADK如何驱动P1嘌呤信号异常？后者又如何作用于GABA信号而促进癫痫的形成与发展？两个关键问题进行探讨。本项目的实施将为癫痫发病机制研究增添新的实验室证据。

中文关键词： 癫痫；腺苷激酶；γ-氨基丁酸；腺苷A1受体；P2X7受体

英文摘要： Adenosine can terminate epileptic seizure through inhibition of the excitatory transmitter. Therefore, adenosine is called"endogenous antiepileptic substance". Adenosine kinase is the mainly regulatory enzyme for adenosine metabolism. In acute seizures, ADK expression showed sharp delines to cause sharp increase of adenosine concentration and activation of P1 purinergic receptors and seizure termination. However, we found different change direction of ADK and P1 purinergic receptors in chronic recurrent epilepsy rats through our preliminary work. We suppose this reverse change is the reason for changing the effect of adenosine from antiepileptic to epileptogenic. ADK drived abnormal adenosine concentration and P1 purinergic singnal is probably an important epileptogenic mechanism. Meanwhile, scientific study revealed GABA signal pathway of neurons was the important target of purinergic signal and ADK was mainly expressed by glias. Therefore, neuron-glia cross talk linked by purinergic signal pathway might be deep epileptogenic mechanism. Our project will be carried out through both in vivo and in vitro aspects through core technologies of genetic engineering, electrophysiology and antagonist/agonist. We will focus on two critical issues: How can ADK drive the abnormality of P1 purinergic signal? and how P1 purin

英文关键词： epilepsy；adenosine kinase；GABA；adenosine A1 receptor；P2x7 receptor