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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：
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
项目类别：
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

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.

项目总结