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:10387155
- 负责人:
- 金额:$ 55.08万
- 依托单位:
- 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:
- 关键词:AddressAdultAmputationApoptosisAutomobile DrivingCardiacCardiac MyocytesCause of DeathCell CycleCellsCentromereCessation of lifeCicatrixCoronary VesselsCytokinesisEndocardiumEpicardiumEventExcisionFOXM1 geneFailureG2/M TransitionGene ExpressionGenesGoalsHealthHeartHeart DiseasesHeart InjuriesHeterogeneityIn SituInfarctionInjuryM cellMetabolicMitosisModelingMolecularMolecular GeneticsMutationMyocardialMyocardial InfarctionNatural regenerationNecrosisPathway interactionsPopulationProcessProliferatingProteinsRecording of previous eventsRegenerative responseResectedRoleSocietiesTestingTissuesTranscription CoactivatorVentricularZebrafishaurora B kinasecardiac regenerationcardiac repaircdc Genescell injurycoronary vasculaturecyclin B3forkhead proteinheart functioninjuredloss of functionmutantnovel strategiesnovel therapeuticsprematurepreventrepairedresponseresponse to injurysingle-cell RNA sequencingtranscriptometranscriptome sequencingubiquitin-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
项目成果
期刊论文数量(0)
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Michael WaiKok Tsang其他文献
Michael WaiKok Tsang的其他文献
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{{ truncateString('Michael WaiKok Tsang', 18)}}的其他基金
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:
10541219 - 财政年份:2022
- 资助金额:
$ 55.08万 - 项目类别:
Delineating the Role of FGF Signaling and Vertebrate Heart Development
描述 FGF 信号传导和脊椎动物心脏发育的作用
- 批准号:
7842096 - 财政年份:2009
- 资助金额:
$ 55.08万 - 项目类别:
Delineating the Role of FGF Signaling and Vertebrate Heart Development
描述 FGF 信号传导和脊椎动物心脏发育的作用
- 批准号:
7636848 - 财政年份:2008
- 资助金额:
$ 55.08万 - 项目类别:
Delineating the Role of FGF Signaling and Vertebrate Heart Development
描述 FGF 信号传导和脊椎动物心脏发育的作用
- 批准号:
8268987 - 财政年份:2008
- 资助金额:
$ 55.08万 - 项目类别:
Delineating the Role of FGF Signaling and Vertebrate Heart Development
描述 FGF 信号传导和脊椎动物心脏发育的作用
- 批准号:
7810737 - 财政年份:2008
- 资助金额:
$ 55.08万 - 项目类别:
Delineating the Role of FGF Signaling and Vertebrate Heart Development
描述 FGF 信号传导和脊椎动物心脏发育的作用
- 批准号:
7515926 - 财政年份:2008
- 资助金额:
$ 55.08万 - 项目类别:
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