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WNT SIGNALING IN CARDIAC CONDUCTION AND ARRHYTHMOGENESIS

心脏传导和心律失常中的 WNT 信号传导

基本信息

批准号：
9198256
负责人：
STACEY Lynn RENTSCHLER
金额：
$ 38.39万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198256
关键词：
Address Adipocytes Adipose tissue Adult Area Arrhythmia Binding Biological Assay Bone Morphogenetic Proteins Cardiac Cardiac Myocytes Cell Lineage Cells Child Congenital Heart Defects Connexins Data Defect Deposition Development Diagnostic Disease Electrophysiology (science)Embryo Embryonic Heart Enhancers Ensure Foundations Future Gap Junctions Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genetic Variation Genomic Segment Heart Heart Atrium Human In Vitro Ion Channel Maintenance Massive Parallel Sequencing Measures Mediating Modeling Morbidity - disease rate Morphogenesis Morphology Mutagenesis Mutant Strains Mice Myocardial Myocardium Optics Pathway interactions Pattern Phenotype Phosphorylation Post-Translational Protein Processing Publications Regenerative Medicine Regulation Regulatory Element Resolution Role Signaling Protein Site Sodium Channel Structure Sudden Death Syndrome Techniques Testing Therapeutic Tissues Tricuspid Atresia Tricuspid valve structure Ventricular WNT Signaling Pathway Wolff-Parkinson-White Syndrome Work base beta catenin cell type chromatin immunoprecipitation design electrical property genetic manipulation genetic predictors genome wide association study genome-wide in vivo loss of function migration mortality mouse model mutant novel postnatal programs protein expression public health relevance transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The atrioventricular canal is an important structure in the embryonic heart, involved in valve formation and in coordinating electrical impulse delay to ensure sequential activation and contraction of the atria and ventricles. Here we seek to understand how canonical Wnt signaling regulates the electrical programming of the atrioventricular (AV) junction through its regulation of ion channel gene expression and cardiac conduction. This area of study is significant because congenital and acquired arrhythmias, important causes of morbidity and mortality, may result from altered programs of gene expression that influence ion channel gene expression and cardiac conduction. Loss of canonical Wnt signaling within embryonic myocardium results in congenital heart defects involving the AV junction, including tricuspid valve atresia. Here we will investigate the mechanism for how Wnt signaling regulates morphologic development of the AV junction, as well as the electrical patterning of this tissue, with the following aims: 1. Delineate the mechanisms by which myocardial Wnt signaling regulates atrioventricular canal morphogenesis. Using genetic mouse models to perform gain- and loss-of-function of canonical Wnt signaling, we will assess the role of Wnt in regulating the proliferation, migration and differentiation of epicardial and endocardial cells within the AV junction. We will elucidate whether Wnt signaling is required for postnatal maintenance of the AV junction, and whether Wnt activation is sufficient to induce ectopic AV junctions in the postnatal heart. 2: Identify direct targets of canonical Wnt signaling that promote an atrioventricular junction phenotype. Based on our preliminary data, Wnt globally regulates the phenotype of the AV junction. We will perform chromatin immunoprecipitation (ChIP) for β-catenin, the key transcriptional effector of Wnt signaling, as well as enhancer mutagenesis assays, to determine how Wnt regulates the expression of the transcription factor Tbx3. We will perform RNA-sequencing and ChIP followed by massively parallel DNA sequencing (ChIP-seq) to identify novel putative downstream Wnt target genes and their regulatory elements. 3: Elucidate the mechanisms for Wnt-mediated regulation of cardiac conduction. Our preliminary data demonstrate that perturbation of Wnt signaling during development alters AV conduction and expression of sodium channels and gap junctions. Using ChIP-qPCR in gain- and loss-of-function mouse mutants, we will determine how sodium channel expression is regulated by Wnt signaling We will determine whether altered ventricular conduction velocity in Wnt mutant mice is associated with changes in Nav1.5 and/or gap junction protein expression and phosphorylation. Using optical mapping techniques, we will elucidate whether Wnt signaling dynamically regulates cardiac conduction in the adult heart.

描述(申请人提供)：房室管是胚胎心脏的一个重要结构，参与瓣膜的形成和协调电脉冲延迟，以确保心房和心室的顺序激活和收缩。在这里，我们试图了解规范的Wnt信号如何通过调节离子通道基因表达和心脏传导来调节房室交界处的电程序。这一领域的研究意义重大，因为先天性和获得性心律失常是发病率和死亡率的重要原因，可能是由于影响离子通道基因表达和心脏传导的基因表达程序改变造成的。胚胎心肌中规范的Wnt信号的丢失会导致涉及房室交界处的先天性心脏缺陷，包括三尖瓣闭锁。在这里，我们将研究Wnt信号如何调节房室交界处的形态发育以及该组织的电模式，目的如下：1.阐明心肌Wnt信号调节房室管形态发生的机制。利用小鼠遗传模型研究Wnt信号的功能变化，我们将评估Wnt在房室交界处调控心外膜和心内膜细胞的增殖、迁移和分化中的作用。我们将阐明Wnt信号是否需要出生后维持房室连接，以及Wnt激活是否足以在出生后心脏诱导异位房室连接。2：确定促进房室交界区表型的典型Wnt信号的直接靶点。根据我们的初步数据，Wnt在全球范围内调节房室连接的表型。我们将对Wnt信号的关键转录效应因子β-Catenin进行染色质免疫沉淀(ChIP)和增强子突变分析，以确定Wnt如何调节转录因子Tbx3的表达。我们将进行RNA测序和芯片后大规模并行DNA测序(CHIP-SEQ)，以确定新的假定下游Wnt靶基因及其调控元件。3.阐明Wnt介导的心脏传导调节机制。我们的初步数据表明，Wnt信号在发育过程中的扰动改变了房室传导和钠通道和缝隙连接的表达。在功能获得和功能丧失的小鼠中使用芯片定量聚合酶链式反应，我们将确定钠通道的表达如何受到Wnt信号的调节。我们将确定Wnt突变小鼠的心室传导速度改变是否与NaV1.5和/或缝隙连接蛋白表达和磷酸化的变化有关。利用光学标测技术，我们将阐明Wnt信号是否动态地调节成人心脏的心脏传导。