腺苷A2A受体激活RhoA/ROCK2信号通路破坏神经元骨架促进颅脑创伤后认知障碍的机制研究

项目名称： 腺苷A2A受体激活RhoA/ROCK2信号通路破坏神经元骨架促进颅脑创伤后认知障碍的机制研究

项目编号： No.81201461

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学四处

项目作者： 宁亚蕾

作者单位： 中国人民解放军第三军医大学

项目金额： 23万元

中文摘要： 认知障碍是创伤性脑损伤(TBI)的常见后遗症，目前尚缺乏有效对因治疗手段。神经元结构完整和突触有效传递是认知活动的基础，TBI后神经元骨架破坏是抑制神经突再生及突触形成和功能进而引起认知障碍的关键。腺苷A2A受体(A2AR)是神经精神活动及TBI后各种继发性损伤的重要调控因子，我们前期发现颅脑创伤后A2AR能促进ROCK2表达及记忆损害，而RhoA/ROCK2是调节细胞骨架的重要通路，故推测TBI后A2AR可能激活该通路引起神经元骨架破坏而促进认知障碍的发生。本研究拟首先在培养的神经元中证明RhoA/ROCK2活化是A2AR激活破坏神经元突起进而影响突触形态和功能的重要机制；并利用A2AR基因敲除动物和药理学干预，观察调控A2AR对RhoA、ROCK2及下游底物水平和活性以及TBI后树突、轴突和突触形态、数目和功能及认知功能的影响，为临床治疗提供理论依据及新的思路和选择。

中文关键词： 创伤性脑损伤；腺苷A2A受体；认知障碍；神经元；ROCK2

英文摘要： The disruption of brain function such as cognition deficit is dominant syndrome after traumatic brain injury (TBI). So far, there is little available therapeutic treatment against the pathogenesis. Neuronal morphological integrity and effective synaptic transmission are basis of cognition. During the period of traumatic brain injury, destruction of neuronal cytoskeleton is the key event for inhibition of the neurite regeneration and the synapse formation and function and thus promotion of cognitive dysfunction. The adenosine A2A receptor (A2AR), one of the most important modulators for both neuropsychiatric and secondary brain injuries, is also involved in cytoskeletal organization. Besides, we previously demonstrated that activation of the A2AR exacerbated cognitive impairment and increased the activity of ROCK2, the key molecule that regulating cytoskeleton formation and cell motility after explosive blast-induced neurotrauma. Therefore, it is possible that activation of A2AR induces neuronal cytoskeleton destruction via ROCK2 signaling and thus exacerbated cognitive impairment following traumatic brain injury. Hence, the first objective of this proposal is to identify that activation of ROCK2 is a vital mechanism involved in A2AR stimulation-promoted neurite damages and synapse abnormalities in cultured corti

英文关键词： traumatic brain injury；adenosine A2A receptor；cognitive dysfunction；neuron；ROCK2