SORBS2高表达介导的细胞周期停滞参与左室心肌致密化不全心肌病的机制研究

左室心肌致密化不全心肌病（LVNC）是一种心肌发育不良的心肌病，其特征为肌小梁过度增生，诱发心功能不全，目前机制尚不清楚。有研究表明心肌细胞周期停滞，会导致发育及致密化进程受损，从而形成LVNC。前期发现，SORBS2在LVNC疾病心肌组织中特异性升高，并且SORBS2与调节细胞周期的Notch通路和14-3-3蛋白密切相关。我们假设SORBS2的高表达可以影响Notch通路活性以及14-3-3表达，继而导致细胞周期停滞，从而出现LVNC。本项目通过SORBS2心肌过表达小鼠模型从两个方面来探索SORBS2在LVNC的致病机理：1）观察SORBS2心肌过表达的小鼠胚胎以及成年小鼠心脏的发育情况；2）分析SORBS2过表达小鼠心脏的心肌细胞周期相关通路的改变以及如何对细胞周期如何调控。本研究将阐明SORBS2如何介导心肌细胞周期停滞来参与LVNC的发生与发展，从而为LVNC开发新的治疗靶点。

Left ventricular noncompaction (LVNC) is a kind of cardiomyopathy with myocardial dysplasia, which is characterized by hyperplasia of ventricular trabecula, and then results in cardiac dysfunction. However, the mechanism of LVNC still remain unclear. Studies have shown that the cardiac muscle cell cycle is stagnated, leading to impaired development and densification process, thus forming LVNC. Previous results from us showed that the SORBS2 is uniquely upregulated in LVNC disease and SORBS2 was highly related to cell cycle regulators including Notch signaling pathway and 14-3-3 protein. We hypothesized that the high expression of SORBS2 protein could impair Notch pathway activity and 14-3-3 protein expression, leading to cell cycle arrest and the occurrence of LVNC. In our project, the pathogenic mechanism of SORBS2 in LVNC was explored from two aspects through mouse model of cardiac specific overexpression of SORBS2: 1) The development of embryonic and adult mouse hearts and the maturation degree of cardiomyocytes dense layer in mouse model of cardiac specific overexpression of SORBS2; 2) To analyze the changes of cardiomyocyte cycle related pathways in the hearts from mice with cardiac-specific overexpression of SORBS2. To further analyze how SORBS2 regulates the cell cycle of cardiomyocytes through Notch pathway and 14-3-3 protein. This study will clarify how SORBS2 mediates cardiac cell cycle arrest to participate in the occurrence and development of LVNC, so as to develop a new therapeutic target for LVNC.