Grant: Operating Grant

In the heart, muscle contraction is triggered by the release of calcium from the internal calcium stores called the sarcoplasmic reticulum, whereas muscel relaxation is achieved by moving the released calcium back to the the stores. To ensure stable muscle contraction and relaxation, i.e. heart beats, calcium release and reuptake must be precisely controlled. However, in some pathological settings, this calcium cycling is disturbed, leading to alternating changes in calcium release and musche contraction in a beat-to-beat basis, a phenomenon known as calcium alternans that can cause electrical alternans in the heart, resulting in irregular heart beats and sudden death. At the moment, the mechanism underlying these beat-to-beat variations is unclear. The objective of this research proposal is to investigate how alternating changes in calcium release occurs and how defects in the calcium release channel lead to calcium release alternations and irregular heart beats. Recent studies from Dr. Chen's laboratory have provided some important clues to these fundamental questions. A variety of cutting-edge technologies will be employed to study the role of the channel in controlling calcium release and how this process is affected by disease-causing mutations in the channel. These proposed studies will shed novel and exciting insights into the molecular basis and regulation of Ca2+ release, and have profound implications for the prevention and treatment of various heart diseases.