Virus infection can cause inflammation of the heart muscle, termed viral myocarditis, ultimately leading to enlarged heart and heart failure. Viral myocarditis and its long-term consequences are among the most common causes of disease and death in China and North America, particularly in children. Enteroviruses, such as coxsackievirus B3 (CVB3), are the most prevalent viruses associated with this disease. There is currently no specific treatment available for viral myocarditis. The tumor-suppressor protein p53 plays a pivotal role in the induction of cell death and the repression of virus replication. Our previous studies have shown that CVB3 infection leads to a loss of the p53 protein, suggesting that the virus may maximize its own replication by regulating p53 levels. Indeed, as a joint effort, we have recently demonstrated that REGgamma, a protein degradation activator, is modified during CVB3 infection to support efficient viral replication through facilitating p53 degradation. In this joint proposal, we aim to further explore the interplay between REGgamma and p53 in the progression of viral myocarditis. Three specific aims are proposed: 1) To study the interaction between REGgamma and p53 and the role of such interplay in CVB3 replication in isolated heart cells; 2) To investigate the mechanisms of how p53 regulates CVB3 replication in isolated heart cells; and 3) To determine the severity and progression of CVB3-induced myocarditis in genetically engineered moue models to examine the significance of REGgamma or p53 loss in virus-induced infection and damage of the heart. These studies will provide novel insights into the mechanisms of CVB3 infection and will assist in the development of new therapeutic approaches against viral myocarditis, greatly impacting on health care in both China and Canada.