Mechanisms controlling epicardial-dependent promotion of heart regeneration in zebrafish.
控制斑马鱼心外膜依赖性促进心脏再生的机制。
基本信息
- 批准号:10650811
- 负责人:
- 金额:$ 42.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-05 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAblationAddressAdultAllelesBacterial Artificial ChromosomesBinding SitesBiological AssayBiologyCandidate Disease GeneCardiac MyocytesCell ProliferationCell SeparationCell TransplantationCellsChromatinCicatrixClinicalCollagenCoronaryEnvironmentEpicardiumGene Expression RegulationGenesGeneticHeartHeart BlockHeart InjuriesHeart failureHumanImpairmentIncidenceInjuryKnock-inKnowledgeLabelMammalsMapsMediatingMesothelial CellMitogensModelingMolecularMutateMyocardial InfarctionMyocardiumNatural regenerationNucleic Acid Regulatory SequencesOutcomeParacrine CommunicationPathway interactionsPatientsPericytesProliferatingRegenerative capacityRegenerative responseRegulatory ElementReporterRoleSignal TransductionSourceSupporting CellSurfaceTestingTranscriptional RegulationTransducersTransgenic OrganismsTransplantationUp-RegulationVascularizationWorkZebrafishangiogenesisattack victimcardiac regenerationcardiac repaircell typegenetic manipulationgenetic signaturegenome-wideheart damageheart functionhuman stem cellsin vivoinhibitorinsightmultipotent cellmuscle regenerationmutantnew therapeutic targetnovelnovel strategiesparacrinepharmacologicprogenitorreceptorregenerativeregenerative therapyresponseresponse to injurysingle-cell RNA sequencingstem cellstherapy developmenttranscriptometranscriptomic profiling
项目摘要
Abstract
The human heart shows little regenerative capacity following an injury such as myocardial infarction (MI).
Instead, the heart scars, decreasing cardiac function, and leading to heart failure. There is no clinically
meaningful regenerative therapy available for MI patients. By contrast, adult zebrafish regenerate heart muscle
after severe cardiac damage without significant scarring. This is achieved through proliferation of existing
cardiomyocytes (CMs), aided by the environment provided by non-muscle cells, such as the epicardium, a
mesothelial cell sheet covering the surface of the heart. An analogous regenerative machinery of CM proliferation
and epicardium contributions also exists in the adult mammalian heart; however, it is not sufficiently activated
for significant regeneration. Recent studies demonstrated that restoring epicardial factors through the application
of epicardial patches or co-transplantation of human stem cell-derived epicardial cells together with stem cell-
derived CMs after an MI benefit heart regeneration. Thus, enhancing the pro-regenerative activation of the
epicardium may benefit mammalian heart regeneration after MI. We and others previously found that the
zebrafish epicardium is activated by injury and aids muscle regeneration through paracrine effects and as a
source of multipotent cells. However, little is known about the cellular and molecular mechanisms controlling
epicardial activation that lead to successful heart regeneration. To this end, understanding how regenerative
responses of the epicardium are regulated in adult zebrafish will lead to new therapeutic targets that underlie the
regenerative deficiencies in mammals. To address this, using single-cell RNA-sequencing, we have identified a
transient adult epicardial progenitor cell (aEPC) subpopulation within the epicardium after heart injury.
Transplantation assays implicate a capacity of aEPCs to give rise to perivascular cells, which are critical for
coronary revascularization. Genetic ablation of these aEPCs blocks heart regeneration, suggesting an
indispensable role. Pharmacological manipulations and transcriptome analyses yielded candidate genes that
underlie the activation of aEPCs. Further, unbiased genome-wide profiling of chromatin accessibility using
ATAC-seq revealed putative regulatory elements that exert transcriptional regulation of these genes. We
hypothesize that activation of a progenitor cell state in the epicardium underlies successful heart regeneration.
To test this hypothesis, we propose to 1) define the cell fates and functions of the aEPCs in adult zebrafish heart
regeneration using genetic fate mapping, genetic ablation, and single-cell transplantation approaches; and 2)
define the molecular mechanisms underlying aEPC activation through genetic manipulations and analyzing
dozens of transgenic lines and mutants. The outcome of this proposal may ultimately inform approaches for
activating the epicardial progenitors to enhance the limited regeneration displayed in humans after MI.
摘要
人类心脏在心肌梗死(MI)等损伤后几乎没有再生能力。
相反,心脏会留下疤痕,降低心脏功能,导致心力衰竭。在临床上没有
有意义的再生疗法可用于心肌梗死患者。相比之下,成年斑马鱼能再生心肌
在严重的心脏损伤后没有明显的疤痕。这是通过扩展现有的
心肌细胞(CMS),在非肌肉细胞提供的环境的帮助下,如心外膜,
覆盖在心脏表面的间皮细胞薄片。一种类似CM增殖的再生机制
在成年哺乳动物心脏中也有心外膜的贡献,但它还没有被充分激活
以实现显著的再生。最近的研究表明,通过应用恢复心外膜因子
心外膜补片或将人类干细胞来源的心外膜细胞与干细胞共同移植-
心肌梗死后衍生的CMS有利于心脏再生。因此,增强促进再生的激活
心外膜可能有利于心肌梗死后哺乳动物心脏的再生。我们和其他人之前发现
斑马鱼的心外膜被损伤激活,并通过旁分泌效应和作为一种
多能细胞的来源。然而,对细胞和分子机制的控制知之甚少。
心外膜激活,导致成功的心脏再生。为此,了解再生是如何
在成年斑马鱼中,心外膜的反应受到调节,这将导致新的治疗靶点
哺乳动物的再生缺陷。为了解决这个问题,使用单细胞RNA测序,我们识别了一种
心脏损伤后心外膜内的暂时性成人心外膜祖细胞亚群。
移植试验表明aEPC具有产生血管周围细胞的能力,而血管周围细胞对
冠状动脉血运重建。这些aEPC的基因消融阻止了心脏再生,这表明
不可或缺的角色。药理操作和转录组分析产生了候选基因
这是激活aEPC的基础。此外,使用以下方法对染色质可及性进行无偏见的全基因组分析
ATAC-SEQ揭示了对这些基因施加转录调控的假定调控元件。我们
假设心外膜祖细胞状态的激活是心脏再生成功的基础。
为了验证这一假设,我们建议1)确定成年斑马鱼心脏中aEPC的细胞命运和功能
使用遗传命运图谱、基因消融和单细胞移植方法进行再生;
通过基因操作和分析确定AEPC激活的分子机制
数十个转基因品系和突变体。这项提案的结果可能最终会为
激活心外膜祖细胞以增强人类心肌梗死后有限的再生。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Enhancer selection dictates gene expression responses in remote organs during tissue regeneration.
- DOI:10.1038/s41556-022-00906-y
- 发表时间:2022-05
- 期刊:
- 影响因子:21.3
- 作者:
- 通讯作者:
Cross-species single-cell comparison of systemic and cardiac inflammatory responses after cardiac injury.
心脏损伤后全身和心脏炎症反应的跨物种单细胞比较。
- DOI:10.1101/2023.03.15.532865
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Cortada,Eric;Yao,Jun;Xia,Yu;Dündar,Friederike;Zumbo,Paul;Yang,Boris;Rubio-Navarro,Alfonso;Perder,Björn;Qiu,Miaoyan;Pettinato,AnthonyM;Homan,EdwinA;Stoll,Lisa;Betel,Doron;Cao,Jingli;Lo,JamesC
- 通讯作者:Lo,JamesC
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jingli Cao其他文献
Jingli Cao的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jingli Cao', 18)}}的其他基金
Spatiotemporal regulation of polyploidy in zebrafish cardiac tissue regeneration
斑马鱼心脏组织再生中多倍体的时空调控
- 批准号:
10736051 - 财政年份:2023
- 资助金额:
$ 42.38万 - 项目类别:
Mechanisms controlling epicardial-dependent promotion of heart regeneration in zebrafish.
控制斑马鱼心外膜依赖性促进心脏再生的机制。
- 批准号:
10445041 - 财政年份:2021
- 资助金额:
$ 42.38万 - 项目类别:
Mechanisms controlling epicardial-dependent promotion of heart regeneration in zebrafish.
控制斑马鱼心外膜依赖性促进心脏再生的机制。
- 批准号:
10298630 - 财政年份:2021
- 资助金额:
$ 42.38万 - 项目类别:
相似海外基金
Targeted ablation of cerebral atherosclerosis using supramolecular self-assembly
利用超分子自组装靶向消融脑动脉粥样硬化
- 批准号:
24K21101 - 财政年份:2024
- 资助金额:
$ 42.38万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
心房細動に対するPulsed Field Ablationの組織創傷治癒過程を明らかにする網羅的研究
阐明房颤脉冲场消融组织伤口愈合过程的综合研究
- 批准号:
24K11201 - 财政年份:2024
- 资助金额:
$ 42.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
遅延造影心臓MRIによる心房細動Ablation冷却効果の比較:28 vs. 31 mm Cryoballoon
使用延迟对比增强心脏 MRI 比较房颤消融冷却效果:28 毫米与 31 毫米 Cryoballoon
- 批准号:
24K11281 - 财政年份:2024
- 资助金额:
$ 42.38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
InSPACE-VT_Development and Validation of Virtual Pace Mapping to Guide Catheter Ablation of Ventricular Tachycardia
InSPACE-VT_虚拟起搏测绘的开发和验证以指导室性心动过速导管消融
- 批准号:
EP/Z001145/1 - 财政年份:2024
- 资助金额:
$ 42.38万 - 项目类别:
Fellowship
CAREER: Heat Penetration Depth and Direction Control with Closed-Loop Device for Precision Ablation
职业:利用闭环装置控制热穿透深度和方向,实现精确烧蚀
- 批准号:
2338890 - 财政年份:2024
- 资助金额:
$ 42.38万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334777 - 财政年份:2024
- 资助金额:
$ 42.38万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334775 - 财政年份:2024
- 资助金额:
$ 42.38万 - 项目类别:
Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
- 批准号:
2334776 - 财政年份:2024
- 资助金额:
$ 42.38万 - 项目类别:
Continuing Grant
Cryo laser-ablation system (157+193nm) with 'triple-quad' plasma mass spectrometer, Cryo-LA-ICPMS/MS
带有“三重四极杆”等离子体质谱仪、Cryo-LA-ICPMS/MS 的冷冻激光烧蚀系统 (157 193nm)
- 批准号:
515081333 - 财政年份:2023
- 资助金额:
$ 42.38万 - 项目类别:
Major Research Instrumentation
MRI: Acquisition of a Laser Ablation - Inductively Coupled Plasma - Triple Quadrupole - Mass Spectrometer (LA-ICP-QQQ-MS) System For Research and Education
MRI:获取用于研究和教育的激光烧蚀 - 电感耦合等离子体 - 三重四极杆 - 质谱仪 (LA-ICP-MS/MS) 系统
- 批准号:
2320040 - 财政年份:2023
- 资助金额:
$ 42.38万 - 项目类别:
Standard Grant