ProNGF调控紧张性抑制对猴脑缺血后运动皮层重组作用机制的研究

项目名称： ProNGF调控紧张性抑制对猴脑缺血后运动皮层重组作用机制的研究

项目编号： No.81472162

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 周沐科

作者单位： 四川大学

项目金额： 72万元

中文摘要： 脑缺血后GABA介导的紧张性抑制（Itonic）增强，被认为是影响卒中后神经可塑性和功能重组，阻碍神经功能康复的重要原因，但其调控机制尚未阐明。前期工作中课题组首次发现脑缺血可上调神经生长因子前体（proNGF）表达，且siRNA干扰proNGF可使GABA水平降低，改善运动功能。而近年研究亦认为proNGF是介导GABA代谢的关键受体。据此我们推测GABA相关Itonic在影响脑缺血后神经重塑过程中可能受到proNGF调控。本课题拟在前期建立的恒河猴脑卒中模型基础上，以proNGF对GABA能Itonic的调控为靶点，以功能磁共振信息、电生理和行为学评估动态追踪脑缺血后的神经重塑和运动网络功能重组为主线，探讨proNGF调控GABA能Itonic在缺血后脑可塑性中的重要作用。研究结果将对进一步揭示脑缺血后神经异常重塑的机制产生非常积极的意义，并最终为疾病的康复提供新的干预靶点。

中文关键词： 神经康复；神经可塑性；神经生长因子前体；脑卒中；γ-氨基丁酸

英文摘要： Stroke is a leading cause of disability, but no pharmacological therapy is currently available for promoting recovery. Cerebral infarction can induce an increased GABA-receptor-mediated tonic inhibition (Itonic) in peri-infarct cortex, which considered to antagonize the neuronal plasticity required for functional recovery after stroke. However, the modulation of GABAergic inhibition after stroke is still unclear. In our previous work, we found for the first time, that unprocessed precursor of nerve growth factor (proNGF) was stably increased following focal cerebral infarction. In addition, when we down-regulated proNGF expression by siRNA, the level of GABA also decreased, which consistent with the current view that proNGF plays a crucial role in GABA modulation. Based on these evidences, we hypothesize that neuronal plasticity following focal cerebral infarction may be influenced by increased proNGF in the peri-infarct zone and GABA-receptor-mediated Itonic may involved in this neurobiological process. We had established a stable acute middle cerebral artery occlusion (MCAO) model in rhesus monkeys in the previous study. In this research, we plan to further our study to determine the contribution of proNGF on the evolution of neuronal plasticity and GABA-receptor-mediated Itonic following focal cerebral infarction in nonhuman primates. Both proNGF overexpression and GABA inhibitors will be conducted on a monkey model of MCAO. Then we will use functional MRI to track the effect of proNGF on the motor cortical plasticity and re-mapping of motor functions. Moreover, its association with Itonic, behavioral manifestations and other molecular biological results will also be analysed. Our result may form an important basis for a better understanding in the pathophysiology of the neuronal plasticity after stroke, and eventually provide the rationale for a novel strategy to promote rehabilitation after stroke.

英文关键词： neural rehabilitation;neuronal plasticity;proNGF;stroke;GABA