由肌浆网钙释放通道 (Ryanodine Receptor，RyR)介导的肌浆网钙流失会导致的肌浆网钙储备不足，在心衰发展中扮演着重要的角色。肌浆网钙流失主要是指发生在舒张期的RyR钙释放，往往与RyR过度活跃有关。Junctophilin-2（JP2）在心衰的发展以及心肌细胞钙调控中扮演着重要的角色。JP2在心衰患者以及心衰动物模型的心肌中显著下调。申请人首次发现敲低JP2可造成严重的钙调节失控并诱发心衰，而后又发现其主要机制之一是影响参与钙离子转运的RyR2和钠钙交换体的活性。最近有研究表明过表达JP2可预防心衰，但是过表达JP2参与钙调控和对抗心衰的机制尚不明朗。本课题将利用过表达JP2的转基因小鼠研究JP2过表达对RyR2和NCX的影响及以上指标在心衰动物模型中的变化，从而阐明JP2过表达在钙调控中的作用以及对抗心衰的机制。我们的研究结果将为心衰治疗提供新的思路。

Heart failure is a disease marked by the impaired ability of cardiac output to meet systemic metabolic demands. Efficient excitation-contraction coupling (ECC) is critical for normal cardiac contractility. Central to ECC are the complex and highly ordered junctional membrane complexes (JMC) where sarcolemmal invaginations known as transverse (T)-tubules are anchored to sarcoplasmic reticulum (SR). Within these 12 nm clefts, voltage gated calcium channel (VGCC) are coupled to SR associated type-2 ryanodine receptors (RyR2). Junctophilin-2 (JP2) is a protein within JMC, and it is often found being down-regulated in patients with heart failure and animal models of heart failure. The applicant's work was the first to discover that acute loss of JP2 in mice led to heart failure accompanied by severe calcium mishandling. The most recent study by the applicant demonstrated that enhanced RyR2 activity and reduced junctional NCX activity caused by the acute loss of JP2 contributed to the severe calcium mishandling. Recently, another group just reported that JP2 overexpression is protective against heart failure induced by pressure overload. However, it is still elusive how JP2 overexpression affects the progress of heart failure and whether it is related to its role in calcium regulation . In this project, by using transgenic mice with cardiac-specific overexpression of JP2 (JP2-OE), we are going to test the following hypotheses: in ventricular myocytes isolated from murine hearts, whether JP2 overexpression alters baseline global calcium handling characteristics; whether JP2 overexpression alters in vivo activity of RyR2 (clusters), whether JP2 overexpression alters NCX activity and finally, following transverse aortic constriction (TAC), whether JP2 overexpression protects the cells from calcium mishandling by re-evaluating the three above-mentioned aspects. By completing this project, we are going to establish a better understanding of the roles of JP2 in the heart, which may facilitate the development of novel therapeutic strategies for heart failure.