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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

基本信息

批准号：
10541219
负责人：
Michael WaiKok Tsang
金额：
$ 54.72万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10541219
关键词：
Acceleration Address Adult Amputation Apical Apoptosis Automobile Driving Cardiac Cardiac Myocytes Cause of Death Cell Cycle Cells Centromere Cessation of life Cicatrix Coronary Vessels Cytokinesis Endocardium Endowment Epicardium Event Excision FOXM1 gene Failure G2/M Transition Gene Expression Genes Genetic Goals Health Heart Heart Diseases Heart Injuries Heterogeneity In Situ Infarction Injury M cell Metabolic Mitosis Modeling Molecular Mutation Myocardial Myocardial Infarction Myocardial Ischemia 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 candidate identification 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 transcriptomic profiling ubiquitin-protein ligase

项目摘要

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心脏病是导致死亡的主要原因，也是社会的重大健康负担，尤其是心肌疾病