Novel Therapeutics for Long QT Syndrome

长 QT 综合征的新疗法

基本信息

批准号：
10705357
负责人：
Masayuki Yazawa
金额：
$ 24.55万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705357
关键词：
Action Potentials Address Adverse effects Agonist Arrhythmia Biological Assay Birth Blood - brain barrier anatomy Brain CDC2 gene Calcium Channel Cardiac Cardiac Myocytes Cell model Chemicals Client Clinical Coughing Coupling Cyclin-Dependent Kinase 5 Dextromethorphan Disease Disease model Electrocardiogram Electrophysiology (science)Excretory function FDA approved Functional disorder Gene Expression Genetic Genetic Models Goals Heart Hepatotoxicity Human Hypoglycemia In Vitro Induced Mutation Infant Ion Channel Lead Life Long QT Syndrome Longevity Metabolism Mitochondria Modeling Molecular Molecular Chaperones Mus Muscle Cells N-Methyl-D-Aspartate Receptors Names Neuraxis Neurons Organ Pancreas Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phenotype Physiological Play Proteins Proteomics Receptor Activation Regulation Reporting Rodent Model Role Selective Serotonin Reuptake Inhibitor Specificity Syndrome Testing Therapeutic Timothy syndrome Tissues Work absorption antagonist autism spectrum disorder base cancer clinical trial design drug candidate drug development drug testing experimental study gain of function mutation genetic approach heart function in vivo induced pluripotent stem cell inhibitor insight insulin secretion mouse model new technology novel therapeutics overexpression prevent receptor binding side effect sigma-1 receptor small molecule stem cell model therapeutic candidate therapeutic target translational applications translational approach translational study trial design voltage

项目摘要

Project Summary: Abnormal ion channel function in heart muscle cells induces cardiac arrhythmias such as long QT syndrome. In preliminary experiments using pharmaceutical approach, we found that activation of Sigma 1 receptor could alleviate the cellular phenotypes in human induced pluripotent stem cell (iPSC) and mouse models of the genetic cardiac arrhythmias. The goal of this study is to examine the molecular mechanism underlying the beneficial effect of Sigma receptor 1 activation on the phenotypes in cardiac ion channel regulation, action potentials, contraction, mitochondrial function and gene expression in the genetic arrhythmia models. We will use human iPSC and rodent models to accomplish our goal. In addition, we will design and develop new Sigma 1 receptor agonists that are more suitable for cardiac arrhythmias, taking advantage of our expertise in medicinal chemistry. Therefore, our translational study will provide new opportunity of drug development for the genetic syndromic disorders.

项目概要：心肌细胞离子通道功能异常会诱发心律失常，例如长QT综合征。在使用药物方法的初步实验中，我们发现Sigma 1受体的激活可以减轻人类诱导多能干细胞 (iPSC) 和小鼠模型中的细胞表型遗传性心律失常。本研究的目的是探讨该现象背后的分子机制 Sigma 受体 1 激活对心脏离子通道调节、作用表型的有益影响遗传性心律失常模型中的电位、收缩、线粒体功能和基因表达。我们将使用人类 iPSC 和啮齿动物模型来实现我们的目标。此外，我们还将设计和开发新的 Sigma 1 受体激动剂更适合心律失常，利用我们的专业知识药物化学。因此，我们的转化研究将为药物开发提供新的机遇。遗传综合症。