Grant: Project Grant

Cardiovascular disease is the leading cause of death, claiming more lives than all forms of cancer combined. A major cause of cardiovascular death is cardiac arrhythmia. Unfortunately, most existing anti-arrhythmic drugs provide little or no survival benefit. Therefore, a better understanding of the molecular basis of cardiac arrhythmia is urgently needed. One of the most lethal cardiac arrhythmias is catecholaminergic polymorphic ventricular tachycardia (CPVT), which is characterized by stress-induced syncope and sudden death. CPVT is primarily linked to mutations in the cardiac ryanodine receptor (RyR2), which account for ~65% of the CPVT cases. However, the genetic basis of a significant portion of CPVT cases (~30%) remains unknown. Recent studies have implicated that hyperactivity in the type 1 inositol 1,4,5-trisphosphate receptor (ITPR1) may contribute to the genesis of CPVT. However, direct evidence for the role of ITPR1 in CPVT is lacking. We have recently identified a number of hyperactive human ITPR1 mutations, indicating that ITPR1 hyperactivity exist in humans. The overall objective of this project is to define the role of ITPR1 hyperactivity in cardiac arrhythmias. To achieve this goal, we will exploit our unique and novel animal models to determine whether ITPR1 hyperactivity alters calcium handling and membrane excitability, and whether ITPR1 hyperactivity increases the propensity for CPVT in mice. We will also determine whether ITPR1 hyperactivity is associated with CPVT and other cardiac arrhythmias in humans. We expect to identify ITPR1 as a novel risk gene for CPVT and other cardiac arrhythmias. We have substantial experience and expertise in the cardiac electrophysiology and calcium handling research. We expect to provide novel insights into the mechanisms underlying irregular heartbeats and sudden death, thereby advancing the knowledge, diagnosis, and treatment of life-threatening cardiac arrhythmias.