Wnt Signaling in Cardiac Conduction and Arrhythmogenesis

项目摘要 Wnt信号通路调节心脏形态发生，并与先天性心脏病有关。 小鼠和人类的疾病。由于先天性心脏病往往与心室 心律失常是该患者人群发病和死亡的常见原因， 分子基础可能最终改善诊断和治疗选择。我们发现很多基因 编码离子通道亚基是发育过程中Wnt转录的靶点，包括主要的钠离子通道亚基。 在心脏中表达的通道和间隙连接同种型。Wnt信号转导的缺失导致心脏 传导，使小鼠易患源自右心室的室性心动过速，即使在 没有结构性心脏缺陷。有趣的是，全球转录变化是高度不同的， Wnt功能丧失小鼠的左、右心室出现明显的电生理变化。 这项建议将寻求阐明基因组调控元件负责差异的权利与左 在Wnt扰动的情况下心室转录的变化。我们假设非编码基因组 指导心室特异性表达模式的元件可能是遗传性心律失常的基础，如Brugada 综合征和主要影响右心室的致血栓性心肌病。具体地第一 目的是阐明Wnt信号调节小鼠Hey 2表达的潜在机制， 右心室，Notch信号调节Hey 2在左心室的表达， 接近。鉴于全基因组关联研究已经将HEY 2附近的非编码变体与 Brugada综合征，对Wnt和Notch反应的调节元件的扰动可能与 人类疾病Wnt信号在成人获得性心脏病如心力衰竭中也失调， 发病率和死亡率的主要原因，其中对它在调节传导和 心律失常易感性在目标2中，我们将确定核β-连环蛋白是否发生变化， 积累，经典Wnt信号的效应，以及它是否与传导变化相关， 临床相关的鼠心力衰竭模型。作为翻译的一步，我们将测量Wnt活性， 来自衰竭和非衰竭心脏的人左心室组织中的核β-连环蛋白积聚，以及 确定有和没有β-连环蛋白的细胞核是否表达不同的转录物。目标3将决定 几种临床相关的GSK 3抑制剂是否在体外抑制钠通道转录并调节 体内传导速度

Project Summary The Wnt signaling pathway regulates cardiac morphogenesis and has been associated with congenital heart disease in both mice and humans. Given that congenital heart diseases are often associated with ventricular arrhythmias, a common cause of morbidity and mortality in this patient population, a better understanding of the molecular basis may ultimately improve diagnostic and therapeutic options. We found that many genes encoding ion channel subunits are Wnt transcriptional targets during development, including the major sodium channel and gap junction isoforms expressed in the heart. Loss of Wnt signaling leads to changes in cardiac conduction that predispose mice to ventricular tachycardia originating from the right ventricle, even in the absence of a structural heart defect. Interestingly, global transcriptional changes are highly distinct between the left and right ventricles in Wnt loss of function mice, paralleling the distinct electrophysiologic changes. This proposal will seek to elucidate genomic regulatory elements responsible for differential right versus left ventricular transcriptional changes in the setting of Wnt perturbation. We hypothesize that non-coding genomic elements directing ventricular-specific expression patterns may underlie inherited arrhythmias such as Brugada syndrome and arrhythmogenic cardiomyopathy which primarily affect the right ventricle. Specifically, the first aim will elucidate the underlying mechanism whereby Wnt signaling regulates Hey2 expression in the murine right ventricle, and Notch signaling regulates Hey2 expression in the left ventricle, using transgenic approaches. Given that genome wide association studies have linked non-coding variants near HEY2 with Brugada syndrome, perturbation of regulatory elements responsive to Wnt and Notch may have relevance to human disease. Wnt signaling is also dysregulated in adult acquired heart diseases such as heart failure, a major cause of morbidity and mortality, where much less is known about its role in regulating conduction and arrhythmia susceptibility. In Aim 2, we will determine whether there are changes in nuclear β-catenin accumulation, the effector of canonical Wnt signaling, and whether it correlates with conduction changes in a clinically relevant murine heart failure model. As a step towards translation, we will measure Wnt activity and nuclear β-catenin accumulation in human left ventricular tissue from failing and non-failing hearts, and determine whether nuclei with and without β-catenin express distinct transcripts. Finally, Aim 3 will determine whether several clinically relevant GSK3 inhibitors inhibit sodium channel transcription in vitro and modulate conduction velocity in vivo.