由JIK介导的JNK/p38MAPK信号通路在PMS肝气逆证海马损伤发生及经前平干预中的作用机制

Premenstrual syndrome is the commonly and frequently encountered disease of child-bearing period women. Liver-qi invasion is its major syndrome that is characterized by typical restless, irritable, spargosis and headachy. Although it is not clearly understood that the PMS pathogenesis basis, liver catharsis too hyperactivity to liver-qi superinverse, on which we have put forward clinical therapy application that have gain significant curative effect by regulating liver method application. In recently discovery, we found regulating liver formula, Jingqianping Granule, can improve the abnormal ethology of anger-out model rat by regulating JIK etc important genes expression of JNK/p38 MAPK pathways. It is well known that regulating liver formula can protect hippocampus against the stressed injury, PMS liver-qi invasion regulating center was located in hippocampus etc brain. These finding suggest that the abnormal active state of JNK/p38 MAPK pathways closely related to the pathogenesis of PMS liver-qi invasion, but lack of correlative research information until now. Based on our previous researches,it is the effective way to elucidate the essence of liver in taking charge of dispersion and regulating emotion by revealing mechanism of JNK/p38 MAPK signal pathway mediated by JIK in the hippocampal damage development of PMS liver-qi invasion and JQP intervention. PMS liver-qi invasion rat model, magnetic resonance imaging, patch clamp and immune-electron microscope double labelling etc technology were used to validate this speculation and TCM theory.

经前期综合征（PMS）是育龄期女性常见多发病，以烦躁易怒、乳房胀痛、头痛为特点的肝气逆证是其主要证型。从肝疏泄太过致肝气上逆病机出发，临床应用调肝法治疗PMS肝气逆证疗效显著，但机制不明。我们前期发现调肝方药经前平通过调节JNK/p38 MAPK信号通路中JIK等信号分子的表达可有效改善愤怒模型大鼠的异常行为学变化。已知调肝方药可以抗应激性海马损伤，PMS肝气逆证调节中枢定位在海马等脑区，提示我们由JIK介导的JNK/ p38 MAPK信号通路活性状态异常可能与PMS肝气逆证发生中的海马功能异常密切相关,但目前国内外缺乏相关研究资料。本课题拟在已有工作基础上，利用PMS肝气逆证大鼠模型，借助于MRI、膜片钳、免疫印迹等现代生物学技术，深入探索JIK介导JNK/p38 MAPK信号通路在PMS肝气逆证海马损伤发生及经前平干预中的作用机制，为揭示"肝主疏泄调畅情志"本质提供新的科学依据。

经前期综合征（PMS）是育龄期女性常见多发病，以烦躁易怒、乳房胀痛、头痛为特点的肝气逆证是其主要证型，肝失疏泄所致肝气上逆为该病中医基本病机，但具体机制不明。已有的报道证实，调肝方药可以抗应激性海马损伤，而JNK/p38 MAPK通路异常激活与海马损伤关系密切。我们前期研究发现介导JNK/p38 MAPK通路的关键抑制因子JIK（TAOK3）mRNA在PMS肝气逆证中表达异常, 调肝方药通过调控JIK表达可以有效纠正大鼠模型的异常行为表现。因此本课题在前期研究基础上，以探索由JIK介导的JNK/p38 MAPK信号通路在PMS肝气逆证海马损伤发生及经前平干预中的作用机制为目的，通过临床患者-模型大鼠-离体细胞三层次实验，借助分子生物学、细胞生物学、血清药理学等现代研究技术，初步明确了PMS肝气逆证患者脑区及病证模型大鼠海马脑区变化特征，首次明确Caspase3、JIK等关键蛋白在PMS肝气逆证中表达特点，并进一步证实由JIK特异性介导的JNK/p38 MAPK信号通路参与该病证病机且是调肝方药的作用靶点，为今后“肝主疏泄调畅情志”作用机制和调肝方药药理研究提供了科学依据和线索。