我们已发现激动或心肌特异性过表达M3受体对心肌缺血、心肌肥厚、心律失常均具有保护作用；证实了M3受体在重大心脏疾病中发挥了关键作用。近期我们发现在小鼠心肌纤维化模型中，心肌组织lncRNA表达谱发生了明显变化；激动M3受体对心肌纤维化有调控作用。然而，M3受体对心肌纤维化的调控机制及lncRNA在其中的具体作用并不十分清楚。本课题揭示lncRNA（M3RANCR）-M3受体对心肌纤维化的调控作用，建立lncRNA-M3受体对心肌纤维化作用的网络，并检测炎症反应、TGF-β1、ERK、p38 MAPK等信号通路在调控心肌成纤维细胞胶原分泌和纤维化进程中的作用；探索干预lncRNA-M3受体网络防控心肌纤维化的新机制。首次探索lncRNA调控M3受体在心肌纤维化中的作用及机制，为重大心脏疾病提供新理论和干预靶点。

We have previously demonstrated the important role of M3 subtype muscarinic acetylcholine receptor (M3R) in major heart diseases, because the agonist of M3R or cardiac specific over-expression of M3R has shown protective roles in cardiac ischemia, cardiac hypertrophy and arrhythmia. More recently, our results showed that M3R is also involved in the regulation of myocardial fibrosis and the lncRNA profile was obviously changed in the mouse. However, whether lncRNA regulates the development of myocardial fibrosis through M3R needs to be clarified. Therefore, the present proposal will first investigate the regulatory role of M3R in myocardial fibrosis and explore whether and how M3R is regulated by its related long non-coding RNAs (lncRNAs); and then set up the regulating network between lncRNA-M3R and myocardial fibrosis, through the inner pathways including inflammation, TGF-β1, ERK, and p38 MAPK signaling pathways and their subsequently effect on collagen release and fibrosis; finally, we will explore the prevention or rescue of myocardial fibrosis through interference of M3R or M3R associated lncRNA (M3RANCR). This proposal will be the first time to explore the role of M3R and M3RANCR in regulating myocardial fibrosis and its potential mechanisms, which will provide new understanding and intervention target for major heart diseases.