Novel Therapeutics for Timothy Syndrome and Related Cardiac Channelopathy

项目总结： 心肌细胞、神经元和β细胞等可兴奋细胞的钙通道功能障碍可导致致死 心律失常，如Timothy综合征，一种严重的遗传性长QT综合征，也是精神疾病 自闭症和精神分裂症等疾病以及胰岛素分泌异常。在预赛中 通过药学实验，我们发现使用Sigma 1受体激动剂可以激活Sigma 1受体 可以减轻人诱导多能干细胞(IPSC)和小鼠模型的细胞表型 遗传病。这项研究的目的是研究这种有益效果背后的分子机制。 Sigma-1受体激活对离子通道调节、动作电位、线粒体表型的影响 遗传性疾病中的功能和基因表达。我们将使用人类IPSC和啮齿动物模型来完成 我们的目标。此外，我们还将设计和合成新的小分子来开发新的Sigma 1受体 更适合遗传疾病中每种表型的激动剂，利用我们在 药学和药物化学。因此，我们的翻译研究将提供新的机会 治疗遗传性综合征疾病，包括心律失常、自闭症和胰岛素异常的药物开发 分泌物。

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.