miRNA-34a调控JNK信号转导通路干预WIN55，212-2诱导的药物性低温对大鼠心脏骤停全脑缺血的抗炎作用与机制

我们发现WIN55,212-2顺利诱导药物性低温并改善心脏骤停全脑缺血后神经功能障碍，而其分子机制尚未明确。炎性损伤是脑缺血缺氧继发性损伤的主要机制，物理性低温调停JNK等信号通道降低炎性损伤；最新研究示miRNA-34a参与并调控炎症反应，并与多种JNK通道及炎性基因相关联。据此，我们提出miRNA-34a调控JNK通道参与WIN55,212-2诱导药物性低温抗炎的假说。本项目拟：在体外缺血缺氧培养皮层神经元及体内大鼠心脏骤停全脑缺血模型上，结合miRNA-34a和JNK通道研究方法，明确WIN55，212-2诱导药物性低温对miRNA-34a的表达调控，阐明miRNA-34a如何调控JNK炎性信号转导通路，并进一步揭示miRNA-34a调控JNK信号通路在WIN55，212-2诱导药物性低温干预大鼠心脏骤停全脑缺血的抗炎作用，为推动药物性低温的临床进程以及提高疗效新靶点提供理论依据。

We previously demonstrated that WIN55,212-2 could induce mild pharmacological hypothermia, therefore improving the post-cardiac arrest neurological function, however, it remains unclear as to the specific involving molecular mechanism. Inflammatory response after cerebral hypoxia and ischemia has been recognized as the primary mechanism leading to cerebral secondary injury, nevertheless, which could be significantly suppressed by physical hypothermia via JNK signal transduction pathway. Meanwhile, miRNA-34a has been proved to participate in as well as modulate the inflammatory response with the great conncection to genes targeting to JNK pathway or inflammatory citokines. Accordingly, we hypothesize that WIN55,212-2-induced hypothermia played a novel role in anti-inflammation through miRNA-34 via JNK pathway. This protocol is performed in the rat cortical neuron under the condition of hypoxia and ischemia in vitro and in a rat model of post-cardiac arrest global cerebral ischemia in vivo. With the methods of learning miRNA-34a and JNK pathway, this study aims at ascertaining whether the expression of miRNA-34a is regulated by WIN55,212-2-induced hypothermia,demonstrating how miRNA-34a modulates JNK inflammatory signal pathway, and furthermore revealing the role of miRNA-34a in the anti-inflammatory effect of WIN55,212-2 induced hypothermia.The findings of this study potentially would promote the clinical application of pharmacological hypothermia,and also provide reliable basis on new potential interventional target for improving the effectiveness of pharmacological hypothermia.