Grant: Project Grant

In the heart, muscle contraction is triggered by the release of calcium from the internal calcium stores through the calcium release channel, called the ryanodine receptor type 2 (RyR2). It has been well established that enhanced RyR2 activity as a result of gain-of-function (GOF) RyR2 mutations can lead to irregular heart rhythm and sudden death. An increasing body of evidence indicates that suppressed RyR2 activity due to loss of function (LOF) RyR2 mutations can also cause sudden cardiac death. However, the molecular mechanism underlying sudden death caused by LOF RyR2 mutations is largely undefined. Despite their fundamental differences, unfortunately, patients with LOF RyR2 mutations are currently being diagnosed and treated the same way as those with GOF RyR2 mutations. As a result, patients with LOF RyR2 mutations are often misdiagnosed and mismanaged, which may lead to sudden death. Therefore, there is an urgent need to develop effective diagnostic tests and treatments for these patients. The objective of this research proposal is to explore the mechanism, diagnosis, and treatment of heart dysfunction associated with LOF RyR2 mutations. To achieve this goal, we propose to identify and characterize LOF RyR2 mutations and their associated heart defects, to understand the molecular and cellular mechanisms of their actions, and to develop novel diagnostic tests and therapeutic strategies for RyR2 LOF mutation associated diseases. These proposed studies will gain new insights into the mechanism of RyR2 LOF-associated heart dysfunction, and may lead to the development of novel diagnostic tests and treatments for this new entity of heart disease.