Recording the cellular origins of cardiac regeneration

记录心脏再生的细胞起源

• 批准号: 10457815
• 负责人: Clayton Carey
• 金额: $ 7.21万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 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/10457815
• 关键词: Adult; Amphibia; Anatomy; Animal Model; Animals; Atlases; Bar Codes; Behavior; Biological Assay; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiac development; Cell Lineage; Cell physiology; Cells; Cessation of life; Cicatrix; Complex; DNA; 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; 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; cell behavior; cell type; experimental study; heart damage; improved; injured; insight; macrophage; 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

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.

项目概要 人类的心脏在受伤后无法再生，而是用坚硬的心肌替代受伤的肌肉区域 损害心输出量的疤痕组织。促进心肌细胞（CM）增殖，补充受损细胞 心肌是改善生活质量和预防过早死亡的有前途的策略 心肌梗塞康复患者。迄今为止，再生疗法的尝试未能促进 有意义地恢复丢失的心肌。治疗策略的一个有前途的来源涉及以下研究： 具有再生心脏组织的固有能力的脊椎动物，包括斑马鱼模型生物。研究 然而，将非再生哺乳动物与斑马鱼的心脏损伤反应进行比较很困难， 通过巨大的进化分歧。因此需要进行更多与进化相关的比较来确定 区分再生和非再生物种的细胞行为。该提案描述了 旨在识别促进心脏再生的独特遗传和细胞特征的实验 通过与青鳉鱼（一种不可再生的硬骨鱼）的比较来观察斑马鱼。在本次活动的第一个目标中 研究金提案，我将生成斑马鱼和青鳉心脏损伤反应的全器官细胞图谱 通过单细胞 RNA 测序在多个时间点进行分析。对这些数据集的分析将揭示关键细胞如何 再生物种和非再生物种的基因表达模式不同。在第二个目标中， 我利用最近开发的单细胞谱系追踪技术来重建细胞的谱系关系 参与斑马鱼的心脏再生。这些实验将提供一个全面的视图 CM 和免疫细胞被激活以恢复受损组织。在最终目标中，我将检验以下假设： 响应免疫细胞的细胞自主行为促进斑马鱼的心脏再生。我将化验 斑马鱼与造血干细胞相互移植后的心脏再生 青鳉，揭示免疫细胞功能是否足以赋予再生潜力。在一起，这些 实验将为识别确切的细胞群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靶向治疗的模式 促进人类心脏再生。