Recording the cellular origins of cardiac regeneration

记录心脏再生的细胞起源

基本信息

批准号：
10654710
负责人：
Clayton Carey
金额：
$ 7.63万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10654710
关键词：
Adult Amphibia Anatomy Animals Atlases Bar Codes Behavior Biological Assay Cardiac Cardiac Myocytes Cardiac Output Cell Lineage Cell physiology Cells Cessation of life Cicatrix Complex DNA Data Analyses Data Set Development Embryonic Development Fellowship Fishes Future Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Heart Heart Injuries Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Immune Immune response Impairment Injury Label Macrophage Mammals Measures Mediating Methods Modeling Molecular Mus Muscle Myocardial Infarction Myocardium Natural regeneration Organ Oryziinae Outcome Patient-Focused Outcomes Patients Phenotype Population Proliferating Quality of life Recording of previous events Regenerative capacity Route Source Techniques Testing Therapeutic Therapeutic Intervention Time Tissues Ventricular Vertebrates Zebrafish cardiac regeneration cardiogenesis cell behavior cell type experimental study heart damage improved injured insight model organism novel therapeutics premature prevent recruit regeneration potential regenerative regenerative therapy response response to injury restoration single-cell RNA sequencing targeted treatment teleost teleost fish therapy development tool transcriptome

项目摘要

Project Summary Human hearts fail to regenerate after injury, instead replacing injured regions of muscular myocardium with rigid scar tissue that impairs cardiac output. Promoting the proliferation of cardiomyocytes (CMs) to replenish injured heart muscle represents a promising strategy for improving the quality of life and preventing premature death of patients recovering from myocardial infarction. Attempts at regenerative therapies have thus far failed to promote meaningful restoration of lost myocardium. A promising source of therapeutic strategies involves the study of vertebrates with the inherent ability to regenerate cardiac tissue, including the zebrafish model organism. Studies comparing the cardiac injury response in non-regenerating mammals to zebrafish are made difficult, however, by vast evolutionary divergence. More evolutionarily relevant comparisons are therefore needed to determine the cellular behaviors that differentiate regenerating and non-regenerating species. This proposal describes experiments aimed at identifying the unique genetic and cellular features that facilitate cardiac regeneration in zebrafish through comparisons with medaka, a non-regenerating teleost fish species. In the first aim of this fellowship proposal, I will generate organ-wide cell atlases of cardiac injury response in zebrafish and medaka over several time points through single-cell RNA sequencing. Analyses of these datasets will reveal how key cell types differ in their gene expression patterns in regenerating and non-regenerating species. In the second aim, I utilize a recently developed single-cell lineage tracing technique to reconstruct the lineage relationships of cells participating in cardiac regeneration in zebrafish. These experiments will provide a comprehensive view of which CMs and immune cells are activated to restore injured tissue. In the final aim, I will test the hypothesis that the cell-autonomous behaviors of responding immune cells facilitate cardiac regeneration in zebrafish. I will assay heart regeneration following reciprocal transplantations of hematopoietic stem cells between zebrafish and medaka, revealing whether immune cell functions are sufficient to impart regenerative potential. Together, these experiments will provide important steps toward identifying the exact cell populations and gene expression patterns that mediate cardiac regeneration and have the potential to aid in the development of targeted therapies that promote cardiac regeneration in humans.

项目摘要人类心脏受伤后无法再生，而是用刚性代替肌肉心肌的受伤区域疤痕组织会损害心脏输出。促进心肌细胞（CMS）的扩散以补充受伤心肌是改善生活质量并防止过早死亡的有前途的策略从心肌梗塞中康复的患者。到目前为止，尝试再生疗法的尝试未能促进有意义的恢复失去心肌。有希望的治疗策略来源涉及研究脊椎动物具有再生心脏组织的固有能力，包括斑马鱼模型生物。研究但是，将非再生哺乳动物的心脏损伤反应与斑马鱼进行比较，但是很难通过巨大的进化差异。因此，需要更多相关的比较来确定区分再生和非再生物种的细胞行为。该提案描述了实验旨在确定促进心脏再生的独特遗传和细胞特征斑马鱼通过与非再生的硬骨鱼类Medaka进行比较。在第一个目的奖学金提案，我将在斑马鱼和Medaka中生成心脏损伤反应的器官范围的细胞图谱通过单细胞RNA测序在几个时间点上。这些数据集的分析将揭示关键单元格的方式其基因表达模式在再生和非再生物种中的类型不同。在第二个目标中我利用最近开发的单细胞谱系跟踪技术来重建单元格的谱系关系参加斑马鱼的心脏再生。这些实验将提供全面的观点 CM和免疫细胞被激活以恢复受伤的组织。在最终目标中，我将检验以下假设反应免疫细胞的细胞自主行为促进了斑马鱼的心脏再生。我会分析心脏再生在斑马鱼和嗜血瘤之间的造血干细胞的相互移植后 Medaka，揭示了免疫细胞功能是否足以赋予再生潜力。在一起，这些实验将为识别确切细胞群体和基因表达提供重要步骤介导心脏再生并有可能帮助开发有针对性疗法的模式这促进了人类的心脏再生。