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:
- 金额:$ 64.28万
- 依托单位:
- 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:
- 关键词:3-DimensionalAblationAdolescentAdultAnimal ModelCalciumCardiacCardiac MyocytesCardiologyCardiomyopathiesCategoriesCell CommunicationCellsDNA Sequence AlterationData SetDefectDevelopmentDiabetes MellitusEchocardiographyEconomic BurdenElectrocardiogramEmbryoEmbryonic DevelopmentEmbryonic HeartEtiologyExcisionExercise stress testGene Expression ProfileGenesGeneticGenetic ModelsGoalsHealthHeartHeart DiseasesHeart InjuriesHeart VentricleHeart failureHistologicHomeostasisHumanHypertensionImageInflammationInjuryInterventionLabelLifeLigandsMagnetic Resonance ImagingMammalsMapsMesodermMethodsModelingMolecularNatural regenerationNeural CrestNeural Crest CellNeural tubeNeurophysiology - biologic functionPathway interactionsPatternPhenotypePhysiologicalPopulationPositioning AttributePrevalencePreventionRecoveryRegenerative capacityResearchResectedRoleSeriesSignal TransductionStereotypingTestingThallium Myocardial Perfusion Imaging Stress TestToxic effectTransgenic OrganismsVentricularVirus ActivationVirus DiseasesZebrafishcardiac regenerationcardiogenesiscell motilitycell typeclinical diagnosticsexperimental studygene regulatory networkhemodynamicsinsightmutantnotch proteinnovelpharmacologicpopulation migrationpreventprognosticresponsestem cell populationtooltranscription factortranscriptome
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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H. Joseph Yost其他文献
H. Joseph Yost的其他文献
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{{ truncateString('H. Joseph Yost', 18)}}的其他基金
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:
10334528 - 财政年份:2020
- 资助金额:
$ 64.28万 - 项目类别:
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:
9885996 - 财政年份:2020
- 资助金额:
$ 64.28万 - 项目类别:
Genomics Summer Research for Minorities: A Pathway to Promote Diversity in Science Research
少数族裔基因组学夏季研究:促进科学研究多样性的途径
- 批准号:
10190989 - 财政年份:2018
- 资助金额:
$ 64.28万 - 项目类别:
Genomics Summer Research for Minorities: A Pathway to Promote Diversity in Science Research
少数族裔基因组学夏季研究:促进科学研究多样性的途径
- 批准号:
10441307 - 财政年份:2018
- 资助金额:
$ 64.28万 - 项目类别:
Genomics Summer Research for Minorities: A Pathway to Promote Diversity in Science Research
少数族裔基因组学夏季研究:促进科学研究多样性的途径
- 批准号:
9789348 - 财政年份:2018
- 资助金额:
$ 64.28万 - 项目类别:
Genome-wide Analysis of Cardiac Development in Zebrafish
斑马鱼心脏发育的全基因组分析
- 批准号:
7936087 - 财政年份:2009
- 资助金额:
$ 64.28万 - 项目类别:
Genome-wide Analysis of Cardiac Development in Zebrafish
斑马鱼心脏发育的全基因组分析
- 批准号:
8127890 - 财政年份:2009
- 资助金额:
$ 64.28万 - 项目类别:
Genome-wide Analysis of Cardiac Development in Zebrafish
斑马鱼心脏发育的全基因组分析
- 批准号:
8722590 - 财政年份:2009
- 资助金额:
$ 64.28万 - 项目类别:
Genome-wide Analysis of Cardiac Development in Zebrafish
斑马鱼心脏发育的全基因组分析
- 批准号:
8514048 - 财政年份:2009
- 资助金额:
$ 64.28万 - 项目类别:
Genome-wide Analysis of Cardiac Development in Zebrafish
斑马鱼心脏发育的全基因组分析
- 批准号:
8309991 - 财政年份:2009
- 资助金额:
$ 64.28万 - 项目类别:
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