Bdnf基因转录的表观遗传调控在重复经颅磁刺激恢复大鼠脑缺血后神经功能中的作用

项目名称： Bdnf基因转录的表观遗传调控在重复经颅磁刺激恢复大鼠脑缺血后神经功能中的作用

项目编号： No.81471338

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： 周先举

作者单位： 南京医科大学

项目金额： 70万元

中文摘要： 重复经颅磁刺激(rTMS)是一种无痛、无创、安全、有效的治疗技术，具有广泛的临床前景。rTMS治疗作用的生物学机制本质上是促进脑可塑性的改变。NMDA受体以及BDNF在突触可塑性中占核心地位。不同刺激参数如频率和刺激部位的选择对临床治疗至关重要。然而，人们知之很少关于不同频率rTMS如何调节刺激部位以及邻近中枢部位的可塑性的表观遗传机制。我们初步结果显示不同rTMS刺激可分化调节不同脑结构的Bdnf基因外显子表达和NMDA受体在其中的介导作用。本研究通过行为学、形态学和分子生物学等手段将系统探讨高、低频率rTMS在大鼠缺血模型所累及的主要中枢部位如何表观遗传修饰Bdnf基因转录，从而促进神经功能的恢复，以及NMDA 受体和它的主要亚单位NR2A和 NR2B在其中的作用。这个研究计划在前人基础上进一步深入地探讨rTMS治疗的潜在表观遗传机制，为将来广泛应用治疗神经精神疾病提供有力的理论依据。

中文关键词： 重复经颅磁刺激；脑源性神经营养因子；表观遗传；NMDA；受体；脑缺血

英文摘要： In the two recent decades, the rapidly developed repetitive transcranial magnetic stimulation (rTMS) is a painless,non-invasive,safe, effective and convenient treatment technology.It attracts great attention in rehabilitation medicine, psychiatry and neuroscience, and thus has clinically wide application prospect. The therapeutic effects of rTMS fundamentally contribute to brain plasticity, on which the domestic and foreign investigators have done much work. NMDA receptors and brain-derived neurotropic factor (BDNF) play a pivotal role in synaptic plasticity.Different stimulation parameters, such as frequency and stimulation area, are critical for clinical therapy. However, it is little known about how rTMS with different frequencies regulate synaptic plasiticity-related epigenetics at stimulation areas and adjacent areas. Our preliminary results showed that rTMS with different frequencies differentially regulate the expression of Bdnf gene exons at different brain structures, as well as NMDA receptor-mediated effects. By using behavioral, morphological and molecular biological methods, this research proposal is to investigate how different rTMS stimuli epigenetically regulate Bdnf gene transcription in different ischemic central areas (such as the cortex, hippocampus and striatum), and thus promoting the recovery of brain functions.Further, this proposal is to determine the role of the NMDA receptors and its two main subunits (NR2A and NR2B) in the functional recovery of brain ischemia by rTMS.On the grounds of previous studies, this research plan will further explore the underlying epigenetic mechanisms of rTMS therapy and provides a theoretical basis for the future wide application of rTMS to treatment of neurological and mental diseases.

英文关键词： rTMS;BDNF;Epigenetics;NMDA receptors;Ischemia