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

• 批准号: 10558575
• 负责人: H. Joseph Yost
• 金额: $ 64.28万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558575
• 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; Gene Expression Profile; Genes; Genetic; Genetic Models; Goals; Health; Heart; Heart Diseases; Heart Injuries; Heart Ventricle; Heart failure; Histologic; Homeostasis; Human; Hypertension; Image; Inflammation; Injury; Intervention; Label; 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; Phenotype; Physiological; Population; Positioning Attribute; Prevalence; Prevention; Recovery; Regenerative capacity; Research; Resected; Role; Series; Signal Transduction; Stereotyping; Testing; Thallium Myocardial Perfusion Imaging Stress Test; Toxic effect; Transgenic Organisms; Ventricular; Virus Activation; Virus Diseases; Zebrafish; cardiac regeneration; cardiogenesis; cell motility; cell type; clinical diagnostics; experimental study; gene regulatory network; hemodynamics; insight; mutant; notch protein; novel; pharmacologic; population migration; prevent; prognostic; response; stem cell population; tool; transcription factor; transcriptome

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.

项目摘要 成人发作的心肌病和心力衰竭是整个美国的重大健康和经济负担。 预计到2030年，流行率将增加46%。然而，缺乏动物模型， 以测试成人心力衰竭的病因和可能的干预措施。该项目创造了两个新的 成年发病心肌病和心脏衰竭的斑马鱼模型。第一个模型利用交叉 双转基因专门标记神经嵴衍生的心肌细胞（NC-Cms），一小群 典型地定位在心室中的心肌细胞，是正常的心肌细胞形成所需的。 小梁，并持续整个成年生活。我们的双转基因允许专门消融NC-Cm 在生命的任何阶段的谱系;胚胎发育期间的消融导致成人发病的心肌病和心脏病 运动压力测试失败。Notch途径配体jag 2b在NC-Cms中富集。Notch信号传导是 在相邻的中胚层来源的心肌细胞中激活，而不是在NC-Cms中。这些重要的分子 心肌细胞谱系之间的区别导致了第二种模型，jag 2b的遗传突变体， 胚胎小梁形成缺陷和成人心肌病。 与斑马鱼相反，成年哺乳动物在进化上失去了在受伤时再生心脏的能力， 明显缺乏NC-Cms，在进化或发育上丢失。协同分析 斑马鱼和哺乳动物之间的进化差异将是有益的。对心室 切除，缺乏NC-Cms的成年斑马鱼不能再生正常的心脏，这意味着NC-Cms及其 基因调控网络（GRNs）在成人心脏再生。一系列多方面的转基因实验 将测试胚胎来源的NC-Cm谱系的再生要求和NC-Cm的从头激活。 切除心脏中的NC-Cm GRN。这些结果可能会导致通路干预，可以挽救能力 在成年哺乳动物的心脏中再生。 这项研究使用了两种新的斑马鱼模型和各种各样的工具，包括谱系和 时间调节转基因，突变，心脏生理，尖端成像和分子 了解成人型心肌病、心力衰竭和心脏再生病因的方法 在斑马鱼中。本研究将揭示NC-CMS的发育机制和GRN 从邻近的心室心肌细胞中分离出来，这是预防成人心肌病所必需的。 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，以帮助我们了解和治疗人类心脏病。