miR-181a和miR-150调节树突状细胞参与的炎症免疫反应在梗死后心室重构中作用的研究

项目名称： miR-181a和miR-150调节树突状细胞参与的炎症免疫反应在梗死后心室重构中作用的研究

项目编号： No.81470386

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： 姚康

作者单位： 复旦大学

项目金额： 68万元

中文摘要： 炎症免疫反应是心肌损伤后心室重构的关键机制。树突状细胞（DC）是免疫应答启动、调控和维持的重要环节，最近研究发现DC与急性心肌梗死（AMI）后心肌损伤和重构密切相关，但机制不清。本项目从心肌损伤与DC免疫炎症基因表达失控的中间环节- - miRNAs着手，在既往研究基础上，一方面通过体外实验，确立miR-150 和miR-181a对DC免疫功能成熟的影响及对心肌损伤和重构的作用及机制；另一方面通过动物实验，构建条件性DC过表达miRNA小鼠的心梗模型，同时利用CD11c-DTR小鼠建立DC缺失小鼠心梗模型，确立miRNA调节DC参与的炎症免疫反应在心肌损伤和重构中效应与机制；最后通过AMI患者循环miRNA 及DC水平及功能研究，探讨其在心肌损伤与重构中的临床意义。通过本研究，揭示miRNA 调控的DC在AMI心室重构中的关键作用，并进一步拓展其表观遗传调控机制。

中文关键词： 心肌重构；急性心肌梗死；炎症免疫；树突状细胞；miRNA

英文摘要： Activation of the immune inflammation plays an important role during the process of ischemic cardiac injury and remodeling, which includes the production and release of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α),activation of the complement system, production of auto-antibodies, and over-expression of class II major histocompatibility complex molecules. Dendritic cells (DC) initiate the immune inflammation response, but the regulatory function of DC is unclear till now. MicroRNAs (miRNAs) are critical for DC functions, and furthermore, miRNAs are involved in ischemic cardiac injury and anti-injury process. We have found that miR-181a and miR-378 promote the regulatory DC and additionally, these two genes are involved in cardiac remodeling process. Therefore, we put forward the hypothesis that miR-181a/150 promote the modulatory DC, as as to attenuate the ischemic cardiac injury and heart functions. To illuminate this point, firstly, we want to demonstrate the negative regulatory functions and the mechanisms of miR-181a/378 to DC as well as their roles in the ischemic cardiac injury; then, we try to clarify the functions of miRNAs on DC to the ischemic heart, based on the following animal models, myocardial infarction mice, the conditionally knock-in mice of miR-181a/150 in DCs, and the DC-depletion mice (CD11c-DTR); finally, we want to clarify the clinical significance of miRNA on DC function in myocardial infarction patients. In summary, through this project, we try to illuminate a novel epigenetic mechanism in ischemic cardiac injury and anti-injury process mediated by miRNA-induced DC modulation functions. And we also want to demonstrate the great significance of this mechanism so as to improve the clinical management of the ischemic cardiac injury patients.

英文关键词： cardiac remodelling;acute myocardial infarction;immune;dendritic cell;miRNA