CUEDC2调节SERCA2α活性参与心力衰竭发生和进展的机制研究

心衰发病率高，现有治疗手段有限。SERCA2a蛋白水平和活性下降促进心肌细胞“钙失衡”，调控心衰发生和进展。外源性基因表达增强SERCA2a蛋白水平并不能有效改善心功能，提示SERCA2a活性调节更为重要。前期研究发现：缺失CUEDC2蛋白能显著减轻超负荷所致小鼠心功能不全的发生并增强SERCA2a蛋白活性，但确切机制尚不清楚。进一步研究发现CUEDC2蛋白在心衰患者心肌组织中特异性磷酸化。推测：CUEDC2蛋白发生磷酸化，结合PP1，间接增强SERCA2a活性调控蛋白PLB去磷酸化，导致SERCA2a活性下降，调控心衰的发生。研究拟构建心肌细胞特异性CUEDC2敲除小鼠和CUEDC2失活转基因小鼠，在分子、细胞和心脏水平研究CUEDC2在SERCA2a活性调节以及心衰发生中的作用，并以此为基础，研究在体干预CUEDC2对已发心衰的治疗作用。研究期望发现具有原始创新的心衰临床治疗靶标。

The incidence of heart failure was constantly increasing. However, we have limited approach to treat heart failure. Calcium Imbalance, which was promoted by the decrease of SERCA2a protein and activity, is the main cause of the occurrence and progression of heart failure. However, when we delivered the gene coded CUEDC2 into the heart of patients suffered with heart failure, there was no significant of heart function recovery, indicating that the activity of SERCA2a was much more important. In previous study, we found that the heart function is much better in Cuedc2-/- mouse subjected to Transaortic constriction (TAC), and the activity of SERCA2a was much higher than control mouse. However, we don't the exact mechanism about CUEDC2 modulating SERCA2a activity. Recently, we found that the phosphorylation of CUEDC2 was much higher in patients suffered with heart failure. Therefore, we postulated that the phosphorylation of CUEDC2 promotes the dephosphorylation of PLB, and the activity of SERCA2a subsequently decreased. This might be the main cause of heart failure. Based on this postulation, we plan to construct cardiomyocyte specific CUEDC2 knockout mice and constantly phosphorylated CUEDC2. And to study the mechanism of CUEDC2 on SERCA2a regulation on molecular, cellular and heart level. Importantly, we want to test the effect of CUEDC2 knockdown in heart treatment by interfering the protein level of CUEDC2 in mouse with advanced heart failure. Our study might find a novel target of heart failure.