GRK3介导的κ-OR磷酸化信号通路参与调控复苏后心功能的实验研究

项目名称： GRK3介导的κ-OR磷酸化信号通路参与调控复苏后心功能的实验研究

项目编号： No.81201445

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学四处

项目作者： 单怡

作者单位： 中国人民解放军第二军医大学

项目金额： 23万元

中文摘要： 心功能障碍是心脏骤停复苏后死亡的主要原因。我们前期发现心肺复苏大鼠心肌κ-OR蛋白表达水平明显增加，并可能有利于保护心功能。κ-OR属GCPR超家族，GRKs跨膜信号是GCPR信号转导的主要通路，然而κ-OR与GRKs关系研究甚少，虽然有文献指出GRK3是调控κ-OR的上游分子，但尚未见诸心肺复苏研究中。为阐明κ-OR与复苏后心功能的确切关系及GRK3介导的磷酸化信号通路是否参与调控κ-OR的表达和活性并影响复苏后心功能，在原有工作基础上，我们拟从体内和体外两个层面进行实验干预，观察复苏后心肌κ-OR的活性和表达水平变化，并检测GRK3介导κ-OR磷酸化水平及下游分子PI3K/Akt、ERK1/2、p38MAPK、PKA等的变化，结合心功能指标检测，进一步探讨心肺复苏时κ-OR及GRK3介导的受体磷酸化的改变对复苏后心功能的影响与机制，为临床寻求治疗复苏后心功能障碍的方法提供理论基础。

中文关键词： 心肺复苏；心功能障碍；κ阿片受体；GRK3；信号通路

英文摘要： Myocardial dysfunction is the major cause of deaths after cardiac arrest and successful cardiopulmonary resuscitation. We have demonstrated that the kappa opioid receptor (κ-OR) protein expression in myocardium of cardiac arrest and cardiopulmonary resuscitation rats were significant increased. This upregulation of κ-OR may have benefits on myocardial protection.Because κ-OR is member of the G protein coupled receptor superfamily（GCPR）, its biological functions are likely to be modulated by G protein coupled receptors kinases (GRKs) transmembrane signaling pathways.However, little is known about the interaction between κ-OR and GRKs.Although it was showed that κ-OR functions can be modulated by receptor phosphorylation by GRK3, this signaling pathway has not been investigated in the cardiac arrest and cadiopulmonary resuscitation studies.To confirm the interaction between κ-OR and postresuscitation myocardial dysfunction,and futher investigate the effects of GRK3 on modulating κ-OR (both activity and expression) and postresuscitation myocardial dysfunction,we will utilize vivo and vitro models to perform our study. The activity and expression of both total κ-OR and phosphorylated κ-OR in myocaridum will be determined, the signaling pathway of GRK3,κ-OR and its downsteam molecules including PI3K/Akt,ERK1/2,p38MAP

英文关键词： cardiopulmonary resuscitation；myocardial dysfunction；kappa opioid receptor；G protein-coupled receptor kinase-3；signaling pathway