miR-122介导心搏骤停全脑缺血下低温脑保护的新机制

Global cerebral ischemia after cardiac arrest enormously harm to human health. The protective effect of hypothermia on neurological sequelae and mortality for global cerebral ischemia has confirmed by a large number of studies. Bcl-w is the important molecular to regulate apoptosis. Apoptosis has been implicated as playing a key role in prognosis of global cerebral ischemia. Our previous studies established global cerebral ischemia model, the expression of miR-122 in hippocampus were significantly different compared with sham group. In our early clinical trials, miR-122 was found to be down-regulated significantly in blood and closely related to the neurological outcome of patients. Another study observated that miR-122 is the significant predictor of neurological outcome and mortality in patients with cardiac arrest by therapeutic hypothermia. Three MicroRNA analysis softwares indicated that bcl-w is a downstream target of miR-122. We proposes a new hypothesis "Bcl-w targeted by miR-122 may have implications for the effect of hypothermia after global cerebral ischemia. Bcl-w up-regulation by miR-122 inhibitor triggers anti-apoptosis in hippocampus neurons ". In our study,we will base on the hippocampal neurons and global cerebral ischemia model, though pathologic and genetic means, prpbe in the functions of miR-122,which may act as an endogenous apoptosis regulator.Finally, explore the brain protection mechanism of hypothemia and provide a new target and treatment of globle brain ischemic.

心搏骤停全脑缺血致死致残率高，低温保护是目前可靠的脑保护措施，但其保护机制尚不明确。全脑缺血后凋亡调控是神经元转归的关键，bcl-w是凋亡调控的关键因子。我们的前期研究通过芯片筛查及qRT-PCR验证发现全脑缺血低温保护中脑海马组织miR-122表达有显著差异；前期临床试验也发现，患者血液miR-122变化与神经系统预后密切相关，并与另一项研究结果一致，提示miR-122介导全脑缺血低温保护的枢纽作用。靶基因软件分析发现bcl-w为miR-122的下游靶点。本研究提出“miR-122调控bcl-w,介导低温对全脑缺血损伤的神经元凋亡调节作用”的新假说。拟以大鼠海马神经元细胞及全脑缺血动物模型为基础，以荧光素酶及慢病毒载体为工具，以病理结合分子手段，重点探讨全脑缺血损伤低温保护下miR-122的功能及bcl-w下游靶点，力求从全新的视角阐明低温的脑保护机制，为全脑缺血后脑损伤治疗提供新思路。

本项目在全脑缺血低温脑保护的背景下，重点探讨了miR-122 及miR-194的表达差异及功能，研究内容围绕miR-194 的表达降低，对于缺血缺氧条件下神经元的保护作用及调节靶点。研究成果发表SCI第一作者文章3篇，第三作者1篇。另有一篇再投。.重要结果：miR-194能沟通过调节下游靶点SUMO2影响，缺血缺氧条件下的神经元存活。我们通过原位杂交，流式细胞，Westernblot 等手段探讨并验证这条通路的存在。并客观评价了其对于神经元的保护作用。关键性数据见附件。.科学意义：目前国内国际上对于缺血缺氧神经元的保护手段非常有限，神经元非常脆弱，本研究通过自身低温停循环条件下的miRNA ，重点探讨了具有特殊保护作用的miR-194，为未来能够推广到临床，成为有效的治疗手段，提供依据。