Understanding the molecular mechanism of cardiomyocyte dedifferentiation and proliferation during regeneration

了解再生过程中心肌细胞去分化和增殖的分子机制

• 批准号: 10387155
• 负责人: Michael WaiKok Tsang
• 金额: $ 55.08万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387155
• 关键词: Address; Adult; Amputation; Apoptosis; Automobile Driving; Cardiac; Cardiac Myocytes; Cause of Death; Cell Cycle; Cells; Centromere; Cessation of life; Cicatrix; Coronary Vessels; Cytokinesis; Endocardium; Epicardium; Event; Excision; FOXM1 gene; Failure; G2/M Transition; Gene Expression; Genes; Goals; Health; Heart; Heart Diseases; Heart Injuries; Heterogeneity; In Situ; Infarction; Injury; M cell; Metabolic; Mitosis; Modeling; Molecular; Molecular Genetics; Mutation; Myocardial; Myocardial Infarction; Natural regeneration; Necrosis; Pathway interactions; Population; Process; Proliferating; Proteins; Recording of previous events; Regenerative response; Resected; Role; Societies; Testing; Tissues; Transcription Coactivator; Ventricular; Zebrafish; aurora B kinase; cardiac regeneration; cardiac repair; cdc Genes; cell injury; coronary vasculature; cyclin B3; forkhead protein; heart function; injured; loss of function; mutant; novel strategies; novel therapeutics; premature; prevent; repaired; response; response to injury; single-cell RNA sequencing; transcriptome; transcriptome sequencing; ubiquitin-protein ligase

1 Heart disease is the leading cause of death and a significant health burden to society, in particular myocardial 2 infarctions are responsible for a large number of premature deaths world-wide. After a cardiac ischemic event, 3 damaged cells die via necrosis and apoptosis and is replaced by scar tissue. The presence of fibrotic scar tissue 4 diminishes cardiac function and overtime infarcted hearts undergo failure. Recent studies have shown that a 5 limited number of spared cardiomyocytes can dedifferentiate and proliferate in response to injury, but this 6 process fails to sufficiently replace lost cells. However, these studies offer new approaches to stimulate cardiac 7 repair. One clear obstacle is to understand the how mature mammalian cardiomyocytes are restricted from 8 proliferation in the adult hearts. Although the mammalian heart shows limited capacity in repair and regeneration, 9 the adult zebrafish heart is endowed with a robust regenerative response to a variety of injury models. The adult 10 zebrafish heart can efficiently replicate cardiomyocytes, and can stimulate endocardium and coronary vessel 11 regeneration such that damage or lost tissue is completely replaced within weeks. The major goal of this proposal 12 is to understand how the zebrafish heart, specifically cardiomyocytes are activated in response to ventricular 13 injury to dedifferentiate and proliferate. Findings from these studies will provide important factors that are critical 14 for driving completion of cardiomyocyte cell cycle after injury. In preliminary studies, we performed transcriptome 15 profiling (RNA-seq) on ventricular resected hearts and identified a number of genes that are highly expressed 16 following injury. Our studies reveal that one of these genes, the forkhead transcription factor, foxm1 is 17 upregulated in cardiomyocytes that are within the injury border zone. Studies with foxm1 mutant zebrafish 18 showed cardiomyocyte cell cycling was diminished and failure to resolve scar tissue upon ventricular resection. 19 Transcriptome profiling foxm1 mutant hearts show a marked decrease in expression of cell cycle genes involved 20 in G2/M transition suggesting that Foxm1 may be a critical driver of cardiomyocyte cytokinesis. In addition, we 21 have identified candidate foxm1 target genes implicated to be involved in cardiomyocyte differentiation and 22 mitosis. We therefore propose to characterize the molecular control of cardiomyocyte dedifferentiation and 23 proliferation through extensive study of foxm1 and downstream target genes. The findings from these studies 24 will identify new molecular pathways and factors to that have the potential to stimulate repair and regeneration 25 after myocardial infarction to address a societal health burden.

1心脏病是死亡的主要原因，是社会的重大健康负担，特别是心肌 2个梗塞造成了全世界大量过早死亡的原因。心脏缺血事件后， 3受损细胞因坏死和凋亡而死亡，并被疤痕组织取代。纤维化疤痕组织的存在 4减少心脏功能和加班梗塞的心脏发生故障。最近的研究表明 5有限数量的幸运的心肌细胞可以响应伤害来定位和增殖，但这 6过程无法充分替代丢失的单元。但是，这些研究提供了刺激心脏的新方法 7维修。一个明显的障碍是了解成熟的哺乳动物心肌细胞的限制 8成人心中的扩散。尽管哺乳动物心脏的维修和再生能力有限，但 9成年斑马鱼的心脏具有对各种损伤模型的强大再生反应。成人 10个斑马鱼可以有效地复制心肌细胞，并刺激内膜和冠状动脉血管 11再生使损伤或组织损失在几周内完全替换。该提议的主要目标 12是了解斑马鱼心，特别是心肌细胞因心室而激活 13去分化和扩散的伤害。这些研究的发现将提供至关重要的重要因素 14损伤后驱动心肌细胞细胞周期的完成。在初步研究中，我们进行了转录组 在心室切除的心脏上进行15分析（RNA-SEQ），并鉴定出许多高度表达的基因 16后受伤。我们的研究表明，这些基因之一，即叉头转录因子，foxm1是 17在损伤边界区域内的心肌细胞中上调。 FOXM1突变体斑马鱼的研究 18显示心肌细胞循环减少，并且在心室切除时无法解决疤痕组织。 19转录组谱图FOXM1突变体心脏显示出涉及细胞周期基因表达的显着降低 20在G2/m的过渡中，表明FOXM1可能是心肌细胞细胞因子的关键驱动力。另外，我们 21已确​​定候选FOXM1靶基因与心肌细胞分化有关 22有丝分裂。因此，我们建议表征心肌细胞去分化和 23通过广泛研究FOXM1和下游靶基因的增殖。这些研究的发现 24将确定具有刺激修复和再生潜力的新分子途径和因素 25在心肌梗塞后解决社会健康负担。