Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Viral myocarditis and its main sequelae, dilated cardiomyopathy, represent an important cause of cardiovascular morbidity and mortality in North America. Coxsackievirus B3 (CVB3), a member of the Picornaviridae family, is one of the primary causative agents for these diseases. Serum Response Factor (SRF) is a transcription factor that plays a central role in cardiac development and function by regulating various cardiac specific genes important for contractile structure and function. Conditional knockout of SRF genes in genetically engineered mice results in cardiomyopathy underpinning the importance of SRF in maintaining the normal heart structure and function. In our previous study, we have shown that CVB3 infection leads to decrease expression of contractile genes and reduce heart function in mice. Furthermore, our preliminary data suggests that SRF is cleaved in CVB3 infected HeLa cells, mouse cardiomyocytes, and mouse hearts. In this project, our Hypothesis is that coxsackievirus infection leads to SRF cleavage, which contributes to impaired myocardial function and progression to dilated cardiomyopathy by deregulating contractile gene expression. We will test this hypothesis using mouse neonatal cardiomyocytes, a mouse model of myocardial infarction-induced heart failure, and human heart tissues from patients with ischemic heart disease. Our Specific Aims are: 1) To determine the mechanisms of SRF cleavage; 2) To determine the functional significance of SRF cleavage; 3) To determine the role of SRF cleavage inhibition in coxsackieviral myocarditis. We anticipate that abrogation of SRF cleavage can prevent the onset of coxsackievirus-induced cardiac dysfunction. Understanding the role of SRF cleavage in viral myocarditis will provide valuable insights into the mechanisms by which virus infection impairs heart function and will further the development of new therapeutic approaches to ameliorate myocardial damage and progression to dilated cardiomyopathy.