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The Roles of Neural Crest Derived Cardiomyocytes in Adult-Onset Heart Failure and Regeneration

神经嵴源性心肌细胞在成人心力衰竭和再生中的作用

基本信息

批准号：
9885996
负责人：
H. Joseph Yost
金额：
$ 55.53万
依托单位：
UNIVERSITY OF UTAH
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：
2020-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9885996
关键词：
3-Dimensional Ablation Adolescent Adult Animal Model Calcium Cardiac Cardiac Myocytes Cardiology Cardiomyopathies Categories Cell Communication Cells DNA Sequence Alteration Data Set Defect Development Diabetes Mellitus Echocardiography Economic Burden Electrocardiogram Embryo Embryonic Development Embryonic Heart Etiology Excision Exercise stress test Foundations Genetic Genetic Models Genetic Transcription Goals Health Heart Heart Diseases Heart Injuries Heart Ventricle Heart failure Histologic Homeostasis Human Hypertension Image Inflammation Injury Intervention Label Lead Life Ligands Magnetic Resonance Imaging Mammals Maps Mesoderm Methods Modeling Molecular Natural regeneration Neural Crest Neural Crest Cell Neural tube Neurophysiology - biologic function Pathway interactions Pattern Pharmacology Phenotype Physiological Population Positioning Attribute Prevalence Prevention Recovery Regulator Genes Research Resected Role Series Signal Transduction Testing Thallium Myocardial Perfusion Imaging Stress Test Toxic effect Transgenic Organisms Ventricular Virus Activation Virus Diseases Zebrafish cardiac regeneration cardiogenesis cell type clinical diagnostics experimental study health economics heart function hemodynamics insight mutant notch protein novel prevent prognostic regenerative response stem cell population tool transcription factor transcriptome

项目摘要

Project Summary Adult-onset cardiomyopathies and heart failure are significant health and economic burdens throughout the world, with prevalence projected to increase by 46% by 2030. However, there is a paucity of animal models in which to test the etiologies and possible interventions in adult heart failure. This project has created two novel models of adult-onset cardiomyopathy and heart failure in zebrafish. The first model utilizes intersectional double transgenics to exclusively label Neural Crest derived Cardiomyocytes (NC-Cms), a small group of cardiomyocytes that are stereotypically positioned in ventricles, are required for normal patterning of trabeculae, and persist throughout adult life. Our double transgenics allow exclusive ablation of NC-Cm lineages at any stage of life; ablation during embryogenesis results in adult-onset cardiomyopathy and heart failure in exercise stress tests. The Notch pathway ligand jag2b is enriched in NC-Cms. Notch signaling is activated in adjacent mesoderm-derived cardiomyocytes, not in NC-Cms. These important molecular distinctions between cardiomyocyte lineages led to the second model, genetic mutants of jag2b, which have both embryonic trabeculation patterning defects and adult-onset cardiomyopathy. In contrast to zebrafish, adult mammals have evolutionarily lost the ability to regenerate hearts upon injury and apparently lack NC-Cms, lost either evolutionarily or developmentally. Synergistic analysis of these evolutionary distinctions between zebrafish and mammals will be informative. In response to ventricle resection, adult zebrafish lacking NC-Cms fail to regenerate normal hearts, implicating NC-Cms and their gene regulatory networks (GRNs) in adult heart regeneration. A multifaceted series of transgenic experiments will test the regeneration requirements of embryonically-derived NC-Cm lineages and de novo activation of NC-Cm GRNs in resected hearts. These results might lead to pathway interventions that can rescue the ability to regenerate in adult mammalian hearts. The proposed research uses two novel zebrafish models and a wide variety of tools, including lineage and temporally regulated transgenics, mutants, cardiac physiological, cutting-edge imaging and molecular approaches to understand the etiologies of adult-onset cardiomyopathy, heart failure and cardiac regeneration in zebrafish. This research will discover developmental mechanisms and GRNs that make NC-Cms distinct from their neighboring ventricle cardiomyocytes, and that are required to prevent adult-onset cardiomyopathy and facilitate adult heart regeneration. Our goals are to position these zebrafish models to test pharmacological and other interventions in order to contribute to our understanding and treatments of human heart diseases.

项目概要成人发病的心肌病和心力衰竭是整个国家的重大健康和经济负担到 2030 年，患病率预计将增加 46%。然而，目前缺乏动物模型用于测试成人心力衰竭的病因和可能的干预措施。这个项目创造了两个新颖的斑马鱼成人发病的心肌病和心力衰竭模型。第一个模型利用交叉双转基因专门标记神经嵴衍生心肌细胞（NC-Cms），一小群心肌细胞通常位于心室中，是正常模式所必需的小梁，并持续整个成年生活。我们的双转基因技术可独家消融 NC-Cm 生命任何阶段的血统；胚胎发生过程中的消融会导致成人发病的心肌病和心脏运动压力测试失败。 Notch 通路配体 jag2b 在 NC-Cms 中富集。缺口信号是在邻近的中胚层来源的心肌细胞中激活，而不是在 NC-Cms 中激活。这些重要的分子心肌细胞谱系之间的差异导致了第二种模型，即 jag2b 的基因突变体，该模型已胚胎小梁模式缺陷和成人发病的心肌病。与斑马鱼相反，成年哺乳动物在进化上已经失去了受伤后心脏再生的能力，显然缺乏 NC-Cms，在进化或发育上丢失了。这些的协同分析斑马鱼和哺乳动物之间的进化差异将提供丰富的信息。对心室的反应切除后，缺乏 NC-Cms 的成年斑马鱼无法再生正常心脏，这表明 NC-Cms 及其成人心脏再生中的基因调控网络（GRN）。一系列多方面的转基因实验将测试胚胎衍生的 NC-Cm 谱系的再生要求以及从头激活切除心脏中的 NC-Cm GRN。这些结果可能会导致路径干预，从而挽救能力在成年哺乳动物心脏中再生。拟议的研究使用了两种新颖的斑马鱼模型和多种工具，包括谱系和时间调控转基因、突变体、心脏生理学、尖端成像和分子了解成人心肌病、心力衰竭和心脏再生病因的方法在斑马鱼中。这项研究将发现使 NC-Cms 与众不同的发育机制和 GRN 来自邻近的心室心肌细胞，这是预防成人心肌病所必需的并促进成人心脏再生。我们的目标是定位这些斑马鱼模型来测试药理学和其他干预措施，以促进我们对人类心脏病的理解和治疗。