Control of cardiomyocyte cell cycle by REST in heart failure and regeneration
通过 REST 控制心力衰竭和再生中的心肌细胞周期
基本信息
- 批准号:10397428
- 负责人:
- 金额:$ 62.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-15 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAnteriorArteriesBiologyCandidate Disease GeneCardiacCardiac MyocytesCell CycleCellsChIP-seqChromatinCytokinesisDataDevelopmentDiseaseDisease OutcomeEmbryoEmbryonic HeartEpigenetic ProcessGene ActivationGenesGeneticGoalsHeartHeart DiseasesHeart InjuriesHeart failureHumanInheritedInterphase CellKnock-outKnowledgeLabelLeftLigationMolecularMolecular BiologyMorbidity - disease rateMusMyocardialNatural regenerationNeonatalPatientsPhenotypePopulationRE1-silencing transcription factorReporterRepressionResearchResearch Project GrantsResourcesRestRoleSite-Directed MutagenesisSystems BiologyTestingTherapeuticUp-RegulationWorkbasecardiac regenerationcardiac repaircardiogenesiscdc Genescell typecombatcoronary fibrosisfetalfetal reactivitygene networkgene repressiongenome-wideheart functionhistone modificationimprovedimproved outcomeinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocytesinhibitorinjuredinjury and repairinnovationinsightloss of functionmortalitymouse geneticsmouse modelneovascularizationnovelnovel therapeuticsoverexpressionpreventprogramsrecruitregenerative biologyrepairedsingle-cell RNA sequencingtherapeutic targettranscriptome sequencingtranscriptomics
项目摘要
In this research project, we propose to study the molecular mechanisms by which RE1 silencing transcription
factor (REST) regulates cardiomyocyte cell cycle using synergistic approaches of mouse genetics, molecular
and systems biology. Our ultimate goal is to identify potential therapeutic targets to combat heart disease by
promoting cardiomyocyte proliferation to repair the injured adult heart. The adult heart has a limited repairing
capacity, because most adult cardiomyocytes are non-dividing cells. For adult heart regeneration by pre-
existing cardiomyocytes, we need to understand how cardiomyocyte proliferation is controlled, what population
of cardiomyocytes maintains proliferation potential, whether developmental mechanisms of cardiomyocyte
proliferation are re-activated under diseased conditions, and if they can be further enforced. Here we plan to
address these questions by investigating REST functions in the mouse heart, because our recent studies have
identified REST as a new intrinsic regulator of cardiomyocyte proliferation required for embryonic heart
development and neonatal heart regeneration. REST represses the cell cycle inhibitor p21 to maintain
cardiomyocyte cell cycling. REST is also required for the expression of several key cell cycle activators. Based
on these findings, we hypothesize that upregulation of REST may improve the renewal of the injured heart by
modulating the expression of cell cycle genes and regulators to promote cardiomyocyte proliferation. We will
test this hypothesis in two aims. Aim 1 will determine whether forced REST expression in failing hearts
promotes cardiomyocyte cell cycle and improves the disease outcome. We will specifically inactivate REST in
the cardiomyocytes, with or without the p21 inactivation, as well as forced REST expression, to determine
whether REST is required for adult heart repair. Aim 2 will investigate how REST controls cardiomyocyte cell
cycle in normal and failing hearts by studying and comparing the REST regulatory network in the mature
(MYH6+) and immature (MYH7+) cardiomyocytes. We will also study the REST regulatory network by
determining the REST recruitment of different chromatin co-factors for gene activation or repression. This will
be achieved by using the cell-type specific, genome wide REST chromatin immunoprecipitation sequencing
(ChIP-seq) and transcriptomics (RNA-seq) for MYH6+ versus MYH7+ cardiomyocytes from normal or injured
hearts. The human relevance of mouse findings will be ascertained by the functional study of key REST-
regulated genes in the proliferation of cardiomyocytes derived from the human inducible pluripotent stem cells
(iPSC). By completing this project, we will have determined the REST role in promoting cardiomyocyte
proliferation to improve the renewal and function of failing adult hearts. We will have also learned a genetic
regulatory network by which REST regulates adult cardiomyocyte cell cycle and identified new targets for
improving cardiomyocyte proliferation for heart regeneration. The new information will advance our
understanding of cardiac biology and provide a new direction to treat heart failure.
在本研究项目中,我们打算研究RE 1沉默转录的分子机制,
利用小鼠遗传学、分子生物学和细胞生物学的协同方法,
和系统生物学。我们的最终目标是确定潜在的治疗目标,以打击心脏病,
促进心肌细胞增殖以修复受损的成人心脏。成年人的心脏修复能力有限
因为大多数成年心肌细胞是不分裂的细胞。对于成人心脏再生,
现有的心肌细胞,我们需要了解心肌细胞增殖是如何控制的,
的心肌细胞保持增殖潜力,是否心肌细胞的发育机制,
在疾病条件下,如果它们可以进一步加强,增殖就会重新激活。在这里,我们计划
通过研究小鼠心脏中的REST功能来解决这些问题,因为我们最近的研究
确定REST是胚胎心脏所需的心肌细胞增殖的新内在调节因子
发育和新生儿心脏再生。REST抑制细胞周期抑制因子p21,
心肌细胞周期REST也是几种关键细胞周期激活剂表达所必需的。基于
基于这些发现,我们假设REST的上调可能通过以下方式改善受损心脏的更新:
调节细胞周期基因和调节因子的表达以促进心肌细胞增殖。我们将
从两个方面来检验这个假设。目标1将确定是否在衰竭的心脏中强制REST表达
促进心肌细胞周期,改善疾病转归。我们将特别关注
心肌细胞,有或没有p21失活,以及强制REST表达,以确定
成人心脏修复是否需要休息。目的2:研究REST对心肌细胞的调控作用
通过研究和比较成熟的心脏中的REST调节网络,
(MYH6+)和未成熟(MYH 7+)心肌细胞。我们还将研究REST监管网络,
确定用于基因激活或抑制的不同染色质辅因子的REST募集。这将
通过使用细胞类型特异性、全基因组REST染色质免疫沉淀测序来实现
来自正常或损伤的MYH 6+与MYH 7+心肌细胞的ChIP-seq和转录组学(RNA-seq)
心中小鼠发现的人类相关性将通过关键REST的功能研究来确定。
人诱导性多能干细胞心肌细胞增殖调控基因的研究
(iPSC)。通过完成这个项目,我们将确定REST在促进心肌细胞生长方面的作用。
增殖以改善衰竭的成人心脏的更新和功能。我们还将了解到一种基因
REST调控成人心肌细胞周期的调控网络,并确定了新的靶点,
促进心肌细胞增殖以促进心脏再生。新的信息将促进我们的
了解心脏生物学,并为治疗心力衰竭提供新的方向。
项目成果
期刊论文数量(0)
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BIN ZHOU其他文献
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{{ truncateString('BIN ZHOU', 18)}}的其他基金
Molecular signaling in aortic valve development and congenital aortic valve defect
主动脉瓣发育和先天性主动脉瓣缺陷的分子信号传导
- 批准号:
10544023 - 财政年份:2022
- 资助金额:
$ 62.93万 - 项目类别:
Molecular signaling in aortic valve development and congenital aortic valve defect
主动脉瓣发育和先天性主动脉瓣缺陷的分子信号传导
- 批准号:
10364556 - 财政年份:2022
- 资助金额:
$ 62.93万 - 项目类别:
Control of cardiomyocyte cell cycle by REST in heart failure and regeneration
通过 REST 控制心力衰竭和再生中的心肌细胞周期
- 批准号:
10215615 - 财政年份:2020
- 资助金额:
$ 62.93万 - 项目类别:
Control of cardiomyocyte cell cycle by REST in heart failure and regeneration
通过 REST 控制心力衰竭和再生中的心肌细胞周期
- 批准号:
10052875 - 财政年份:2020
- 资助金额:
$ 62.93万 - 项目类别:
Control of cardiomyocyte cell cycle by REST in heart failure and regeneration
通过 REST 控制心力衰竭和再生中的心肌细胞周期
- 批准号:
10604334 - 财政年份:2020
- 资助金额:
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Single Cell RNA-seq to Identify Endocardial Ontogenic Factors for the Heart
单细胞 RNA-seq 鉴定心脏的心内膜个体发育因子
- 批准号:
9769109 - 财政年份:2018
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Molecular and Cellular Mechanisms in Coronary Artery Development and Anomalies
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Deciphering the roles of Nfatc1 in developmental coronary angiogenesis
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8580415 - 财政年份:2013
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