蛋白激酶D调控内质网应激参与糖尿病心肌病心肌细胞凋亡的作用及机制研究

项目名称： 蛋白激酶D调控内质网应激参与糖尿病心肌病心肌细胞凋亡的作用及机制研究

项目编号： No.81470404

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： 葛志明

作者单位： 山东大学

项目金额： 73万元

中文摘要： 心肌细胞凋亡是糖尿病心肌病（DCM）的主要病理改变，也是糖尿病心功能障碍的重要病理生理机制。内质网应激（ERS）是介导DCM心肌细胞凋亡的重要途径。蛋白激酶D（PKD）家族在心血管系统中发挥了重要的调节作用。PKD的激活参与细胞凋亡的调控过程。我们的前期研究显示糖尿病心肌组织中PKD活化表达明显增加。本课题综合国内外研究现状和预实验结果，提出PKD调控ERS相关信号通路诱导心肌细胞凋亡是糖尿病心肌病重要分子机制的假说。拟以2型糖尿病心肌病大鼠模型为基础，探讨PKD对DCM心肌细胞凋亡及心功能的影响，并初步探讨阿托伐他汀的对糖尿病的心肌保护作用是否通过PKD介导。同时，通过腺病毒转染技术，分别在体内及体外实验中诱导PKD基因沉默，进一步探讨ERS相关信号通路在PKD致DCM心肌细胞凋亡中的作用。本课题的实施将为阐明糖尿病心肌病的发生机制提供新的理论依据，为其防治提供新的靶点。

中文关键词： 糖尿病心肌病；蛋白激酶D；内质网应激；细胞凋亡

英文摘要： In human and animal models of diabetes, a heart muscle specific disease in the absence of other vascular pathology has been described, termed diabetic cardiomyopathy (DCM). The pathogenesis of diabetic cardiomyopathy is a chronic and complex process, which is still unclear. Cardiocyte apoptosis as an early cellular event has been considered to play a critical role in the development of diabetic cardiomyopathy. Because myocytes rarely proliferate in adult cardiac muscles, the loss of cardiomyocytes would eventually lead to compromised cardiac function. The persistent ER(endopasmic reticulum) stress can trigger the activation of c-JUN NH2-terminal kinase (JNK) or transcriptional induction of C/EBP homologous protein (CHOP) and/or caspase-12 dependent pathways to promote the initiation of the apoptotic process. Recently, numerous studies have demonstrated that the apoptosis pathway induced by ER stress was involved in the pathogenesis of diabetic heart failure. The protein kinase D (PKD) family is a recent addition to the calcium/calmodulin-dependent protein kinase group of serine/threonine kinases. Increasing evidence now points toward important roles for PKD-mediated signaling pathways in the cardiovascular system. Recent studies suggest that PKD is an important regulator of different intracellular signaling pathways, including cell apoptosis. The persistent activation of PKD in the heart of DCM rat was observed in our preliminary research. Based on the existing studies and our preliminary experimental results, we hypothesize that PKD plays an important role in cardiocyte apoptosis of DCM, and this effect is mediated by ER stress. The present study is designed to explore the effects and underlying mechanisms of PKD activation in DCM. In our study, type 2 DM rats with cardiomyopathy in vivo and rat primary cardiomyocytes in vitro will be used for discussing the relationship between PKD and ERS during the cardiomyocyte apoptosis. Meanwhile, the role of atorvastatin which may inhibit the activation of PKD and reduce the cardiomyocyte apoptosis will be investigated in vivo. This project will provide a new theoretical support in understanding the pathological mechanism of diabetic cardiomyopathy，which may be helpful to provide a novel target for drug discovery and therapeutic intervention of diabetic cardiomyopathy.

英文关键词： diabetic cardiomyopathy;protein kinase D;endoplasmic reticulum stress;cell apoptosis