致心律失常性心肌病中Syndecan-1通过SMAD3调控TGF-β通路致心肌异常纤维化的机制研究

致心律失常性心肌病(AC)是一类遗传性心肌病，其典型表现为心肌细胞被纤维脂肪组织进行性替代，目前发病机制尚不明确。PKP2为该疾病最常见致病基因，PKP2心肌特异性敲低的小鼠成年后心肌出现异常纤维化，mRNA芯片提示Syndecan-1（SDC1）显著降低。前期研究发现，SDC1能抑制AC小鼠的心肌纤维化。机制探索发现SDC1通过调控TGF-β信号通路参与了心肌纤维化的过程。结合文献及预实验：SDC1与TGF-β通路中关键分子SMAD3相互作用抑制下游通路激活。本课题拟在先前研究的基础上，在细胞及动物水平验证SDC1不同表达水平对心肌纤维化的影响，解析AC模型中SDC1通过调控TGF-β信号通路改变心肌纤维化的分子机制，利用免疫沉淀，定点突变技术等多种生物学技术，验证SDC1与SMAD3的相互作用模式及其调控TGF-β信号通路的分子机制。

Arrhythmogenic Cardiomyopathy is a group of hereditary cardiomyopathy, which is the leading cause of sudden death in young people. The classical pathological manifestation of this disease is the gradual replacement of cardiomyocytes to fatty-fibrotic cells. So far the mechanism causing the disease is unknown. Our previous study show that cardiac conditional knockdown of PKP2 mouse develop abnormal cardiac fibrosis, and mRNA sequencing showed Syndecan-1(SDC1) is downregulated. We found SDC1 could inhibit cardiac fibrosis in AC. Mechanical research found SDC1 can regulate TGF-β pathway which is found to be responsible for fibrosis. Along with published research, wo found that SDC1 interacts with SMAD3 to regulate downstream pathway. Our research was to 1.explore diffrent expression level of SDC1 on development of cardiac fibrosis; 2.elucidate the mechanism on how SDC1 regulates TGF-β pathway in devepment of cardiac fibrosis. 3. find how SDC1 interacts with SMAD3 to inhibit downstream TGF-β pathway.