Grant: Operating Grant

Viral myocarditis is an inflammatory disease of the heart muscle caused by virus infection. It can result in enlargment of the heart and ultimately heart failure, and is one of the most common causes of disease and death worldwide, particularly in children. Many clinical cases of viral myocarditis are attributable to coxsackievirus infection. The treatment for this disease is largely limited. The only definitive treatment for dilated cardiomyopathy available is heart transplantation. Serum response factor (SRF), a muscle-enriched protein, is known to play a central role in heart development and function. It regulates the gene levels of heart proteins which control the contraction of the heart. Destruction of SRF has been associated with several heart diseases, including dilated (enlarged) heart and heart failure. We have previously demonstrated that coxsackievirus infection led to a cleavage and subsequent dysfunction of SRF in the heart. Here we hypothesize that cleavage of SRF during coxsackievirus infection plays an important role in the progression of the disease to heart failure. To test this hypothesis, we propose to further investigate the cause of virus-induced SRF cleavage and the functional consequence of SRF destruction. We will utilize both isolated heart cells and genetically engineered mouse models where SRF cleavage products are present in the heart to examine the contribution of SRF cleavage to the damage of the heart. We will also develop a chemical inhibitor to block the cleavage of SRF, to determine whether this will reduce virus-induced heart failure. The successful completion of this project will not only provide valuable insights into the mechanisms of damaged heart function in viral myocarditis, but also facilitate the development of novel therapeutic agents to protect against viral myocarditis and the progression to heart failure.