Novel Therapeutics for Timothy Syndrome and Related Cardiac Channelopathy

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Project Summary: Calcium channel dysfunction in excitable cells, such as cardiomyocytes, neurons and beta-cells, induces lethal cardiac arrhythmias such as Timothy syndrome, a severe form of genetic long QT syndrome, and also psychiatric disorders such as autism and schizophrenia as well as abnormal insulin secretion, respectively. In preliminary experiments using pharmaceutical approach, we found that activation of Sigma 1 receptor using its agonists could alleviate the cellular phenotypes in human induced pluripotent stem cell (iPSC) and mouse models of the genetic disease. The goal of this study is to examine the molecular mechanism underlying the beneficial effect of Sigma 1 receptor activation on the phenotypes in ion channel regulation, action potentials, mitochondrial function and gene expression in the genetic diseases. We will use human iPSC and rodent models to accomplish our goal. In addition, we will design and synthesize new small molecules to develop novel Sigma 1 receptor agonists that are more suitable for each phenotype in the genetic disease, taking advantage of our expertise in pharmaceutical science and medicinal chemistry. Therefore, our translational study will provide new opportunity of drug development for genetic syndromic disorders including cardiac arrhythmia, autism and abnormal insulin secretion.