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Genetic dissection of Cardiac Conduction System homeostasis and regeneration

心脏传导系统稳态和再生的基因剖析

基本信息

批准号：
9740018
负责人：
Jun Wang
金额：
$ 36.62万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9740018
关键词：
Ablation Adult Aging Antibodies Arrhythmia Bioinformatics Biological Assay Calcium Calcium ion Cardiac Function Study Cardiac Myocytes Cardiac ablation Cardiac conduction system Cardiac development Cardiovascular Diseases Cause of Death Cell Death Cell physiology Cells Cessation of life ChIP-seq Data Defect Development Dissection Drug toxicity Electrophysiology (science)Expression Profiling Fibrosis Functional disorder Gene Expression Genes Genetic Genetic Transcription Goals Heart Heart Contractilities Heart Diseases Histology Homeostasis Human Hypertrophy Immunofluorescence Immunologic Impairment In Vitro Infarction Inherited Injury Knock-in Luciferases Methods MicroRNAs Molecular Morbidity - disease rate Mus Mutation Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Natural regeneration Organ Size Pathologic Pathway interactions Patients Periodicity Phosphotransferases RNA Sequences Regulation Reporter Repression Role RyR2 Ryanodine Receptor Calcium Release Channel Sampling Signal Transduction Syndrome Techniques Testing Tissues Toxic effect diphtheria toxin fragment A gain of function genome-wide heart function heart rhythm in vivo insight mortality novel overexpression targeted treatment

项目摘要

Abstract Genetic dissection of Cardiac Conduction System homeostasis and regeneration The cardiac conduction system (CCS) is required for initiating and maintaining regular rhythmic heartbeats. CCS defects commonly give rise to arrhythmia, a leading cause of morbidity and death worldwide. CCS dysfunction can be inherited or acquired due to conditions such as drug toxicity or myocardial infarction. It is imperative to elucidate the molecular mechanisms underlying CCS homeostasis to facilitate development of cardiac therapies. Importantly, these mechanisms are poorly understood owing to numerous technical challenges. Hippo signaling, a pivotal organ size control pathway, inhibits cardiomyocyte proliferation and regeneration. However, the role of Hippo signaling in the CCS is unclear. Here we will determine whether Hippo signaling regulates CCS homeostasis. Additionally, we will identify regulators and targets of Hippo signaling in the CCS. Our preliminary observations revealed that disruption of Hippo signaling in the CCS caused cardiac arrhythmias in mice, suggesting an important role of Hippo signaling in CCS homeostasis. Notably, deletion of Hippo signaling rescued cardiac rhythm and function after CCS cell ablation, suggesting that repression of Hippo signaling protects the CCS from damage. In addition, we identified candidate microRNA regulators and downstream targets of Hippo signaling. Here we propose to investigate the function and molecular regulatory mechanism of Hippo signaling in the CCS through in the following specific aims: 1) To define Hippo signaling function in CCS homeostasis and elucidate the mechanism by which repression of Hippo signaling protects the CCS from damage, 2) Identify upstream microRNA regulators of Hippo signaling in the CCS, and 3) Identify downstream targets of the Hippo pathway that modulate CCS function.

摘要心脏传导系统动态平衡与再生的遗传学解剖心脏传导系统(CCS)是启动和维持有规律的有节奏的心跳所必需的。 CCS缺陷通常会引起心律失常，这是全球发病率和死亡率的主要原因。二氧化碳捕获由于药物中毒或心肌梗死等疾病，功能障碍可能是遗传的或后天的。它是迫切需要阐明CCS动态平衡的分子机制以促进心脏疗法。重要的是，由于大量的技术问题，人们对这些机制知之甚少。挑战。河马信号，一个关键的器官大小控制途径，抑制心肌细胞的增殖和再生。然而，河马信号在CCS中的作用尚不清楚。在这里我们将确定河马是否信号调节CCS的动态平衡。此外，我们将确定河马信号的监管机构和目标 CCS。我们的初步观察显示，CCS中河马信号的中断导致心脏小鼠的心律失常，提示河马信号在CCS动态平衡中起重要作用。值得注意的是，删除河马信号挽救了CCS细胞消融后的心律和功能，提示河马的抑制作用信令保护容器服务免受损坏。此外，我们确定了候选的microRNA调节器和河马信号的下游目标。在此，我们建议研究其功能和分子调控。河马在CCS中的信令机制通过以下具体目的：1)定义河马信令在CCS动态平衡中的作用，并阐明抑制Hippo信号保护 CCS来自损害，2)识别CCS中河马信号的上游microRNA调节因子，以及3)识别调节CCS功能的河马途径下游靶点。