ARVD/C Dysfunction in Human Stem Cell-Derived Cardiac Tissue
人类干细胞来源的心脏组织中的 ARVD/C 功能障碍
基本信息
- 批准号:9251893
- 负责人:
- 金额:$ 40.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAction PotentialsAcuteAdipocytesAdrenergic AgentsAffectArrhythmiaArrhythmogenic Right Ventricular DysplasiaAthleticBehaviorBiochemicalBiological ModelsBiopsyBloodCRISPR/Cas technologyCardiacCardiac MyocytesCardiomyopathiesCell LineCell modelCellsCounselingCouplingCuesD CellsDataDesmosomesDevelopmentDiseaseDisease ManagementDisease PathwayDisease ProgressionDysplasiaElectrophysiology (science)EngineeringExerciseExtracellular MatrixFibroblastsFibrosisFunctional disorderGap JunctionsGenerationsGenesGeneticGenetic Predisposition to DiseaseGoalsGrowthHeartHeart DiseasesHeart failureHereditary DiseaseHeritabilityHistologicHistologyHumanHuman GeneticsImpairmentIncidenceInfiltrationInheritedInstructionLaboratoriesLeadLeft ventricular structureLightLipidsMeasurementMechanicsModelingMutationMyocardiumOutcomes ResearchPathogenesisPatientsPeriodicityPhasePredispositionProcessProteinsRNARight ventricular structureRiskSignal TransductionSkinSliceSodiumSodium ChannelSourceSpecificityStrenuous ExerciseStructural defectSudden DeathSyndromeTestingTissue ModelTissuesTrainingVentricular ArrhythmiaWorkbiophysical propertiescomparison groupdisease phenotypeexperienceheart cellhuman diseasehuman stem cellsimprovedinduced pluripotent stem cellinsightmonolayernew therapeutic targetnon-geneticnovel therapeuticsprobandpublic health relevancescaffoldsimulationsuccesssudden cardiac deaththerapy designtissue support frametool
项目摘要
DESCRIPTION (provided by applicant): Advances in the use of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) have dramatically advanced the study of heritable human genetic cardiac diseases. While these advances will eventually lead to new treatment options and improved patient counseling, these cellular model systems also permit mechanistic insights and provide a platform for modeling human cardiac tissues. The latter is critically important as patients with cardiomyopathies (genetic and non-genetic forms) or heart failure often experience arrhythmias that can result in sudden death. To study the predisposition of genetic disease syndromes to cause arrhythmias in cardiac tissue, iPSC-CMs will be cultivated in engineered heart slices (EHS), developed by our team that recapitulate a natural 3D microenvironment and enable electromechanical interactions among cells and the extracellular matrix. Our EHS support the growth of engrafted iPSC-CMs; provide important topological, biochemical, and mechanical signals to the cells; manifest functional tissue behavior, including coordinated electrophysiological and contractile activity; and can sustain cardiac arrhythmias in a quantifiable manner. In this project, we propose to use EHS to investigate mechanisms underlying the manifestation and progression of arrhythmias that promote sudden death. As a genetic tool for modeling arrhythmias, we will study iPSCs generated from probands of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) that affect proteins of the cardiac desmosome. In patients, this disease is highly pro-arrhythmic and can lead to sudden cardiac death in young athletes. Hence, the goal of this project is to investigate how structural defects promote arrhythmias in EHS. Specifically we will determine if 1) mutations of desmosomal proteins operate in the early concealed phase of AC to impair intercellular mechanical coupling, resulting in abnormal electrical coupling, slowing of electrical conduction, and reentrant arrhythmia, and 2) secondary alterations in sodium channel function also result in slowing of electrical conduction and arrhythmia. The project involves three complementary and related Aims. Aim 1 will examine the importance of syncytial interactions and tissue microenvironment on the expression and progression of the disease phenotype in ARVC iPSC-CMs. Aim 2 will develop models of simulated exercise to determine increased risk of arrhythmia in EHS models of ARVC. Aim 3 will investigate the instructive cues of different native, extracellular matrices on cellular remodeling and tissue- level arrhythmia in EHS models of ARVC. The outcome of this research will shed light on mechanisms of arrhythmia and sudden cardiac death associated with abnormalities of mechanical junctions that operate not only in ARVC but also in other more common forms of cardiomyopathies. Our study on tissue microenvironment and disease progression in the cardiomyocyte represents a critical step towards the identification of primary and ancillary pro-arrhythmic disease pathways that may prove invaluable to the development of new therapies designed to treat heritable cardiac diseases.
描述(由申请人提供):使用诱导多能干细胞衍生的心肌细胞(iPSC-CM)的进展极大地推进了对可遗传的人类遗传性心脏病的研究。虽然这些进展最终将带来新的治疗选择和改善的患者咨询,但这些细胞模型系统也允许机械见解,并为人类心脏组织建模提供平台。后者是至关重要的,因为心肌病(遗传和非遗传形式)或心力衰竭患者经常经历可导致猝死的心律失常。为了研究遗传性疾病综合征在心脏组织中引起心律失常的倾向,iPSC-CM将在工程心脏切片(EHS)中培养,该切片由我们的团队开发,重现了自然的3D微环境,并使细胞和细胞外基质之间的机电相互作用成为可能。我们的EHS支持植入iPSC-CM的生长;为细胞提供重要的拓扑、生化和机械信号;表现功能性组织行为,包括协调的电生理和收缩活动;并且可以以可量化的方式维持心律失常。在这个项目中,我们建议使用EHS来研究促进猝死的心律失常的表现和进展的机制。作为心律失常建模的遗传工具,我们将研究从影响心脏桥粒蛋白质的致心律失常性右心室发育不良/心肌病(ARVC)先证者产生的iPSC。在患者中,这种疾病是高度致敏的,可导致年轻运动员的心脏性猝死。因此,本项目的目标是研究结构缺陷如何促进EHS中的心律失常。具体而言,我们将确定1)桥粒蛋白突变是否在AC的早期隐蔽阶段起作用,以损害细胞间机械耦合,导致异常电耦合,电传导减慢和折返性心律失常,以及2)钠通道功能的继发性改变是否也导致电传导减慢和心律失常。该项目涉及三个相互补充和相关的目标。目的1将检查合胞体相互作用和组织微环境对ARVC iPSC-CM中疾病表型的表达和进展的重要性。目的2将开发模拟运动模型,以确定ARVC的EHS模型中心律失常风险的增加。目的3探讨不同的天然细胞外基质对ARVC EHS模型细胞重构和组织水平心律失常的指导作用。这项研究的结果将揭示与机械连接异常相关的心律失常和心脏性猝死的机制,这些机械连接不仅在ARVC中起作用,而且在其他更常见的心肌病形式中也起作用。我们对心肌细胞中组织微环境和疾病进展的研究代表了识别原发性和辅助性促心律失常疾病途径的关键一步,这可能对开发旨在治疗遗传性心脏病的新疗法非常宝贵。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
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{{ truncateString('LESLIE TUNG', 18)}}的其他基金
Engineered Human Heart Slice for Testing Drug-Induced Arrhythmia
用于测试药物引起的心律失常的工程人体心脏切片
- 批准号:
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- 资助金额:
$ 40.5万 - 项目类别:
Engineered Human Heart Slice for Testing Drug-Induced Arrhythmia
用于测试药物引起的心律失常的工程人体心脏切片
- 批准号:
10593334 - 财政年份:2020
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$ 40.5万 - 项目类别:
Engineered Human Heart Slice for Testing Drug-Induced Arrhythmia
用于测试药物引起的心律失常的工程人体心脏切片
- 批准号:
10250777 - 财政年份:2020
- 资助金额:
$ 40.5万 - 项目类别:
Mechanoelectrical Interactions Between Cardiac Myofibroblasts and Myocytes
心脏肌成纤维细胞和肌细胞之间的机电相互作用
- 批准号:
9204715 - 财政年份:2016
- 资助金额:
$ 40.5万 - 项目类别:
ARVD/C Dysfunction in Human Stem Cell-Derived Cardiac Tissue
人类干细胞来源的心脏组织中的 ARVD/C 功能障碍
- 批准号:
9815578 - 财政年份:2016
- 资助金额:
$ 40.5万 - 项目类别:
ARVD/C Dysfunction in Human Stem Cell-Derived Cardiac Tissue
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- 批准号:
9106007 - 财政年份:2016
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$ 40.5万 - 项目类别:
Mechanoelectrical Interactions Between Cardiac Myofibroblasts and Myocytes
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- 批准号:
9028886 - 财政年份:2016
- 资助金额:
$ 40.5万 - 项目类别:
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- 批准号:
8259042 - 财政年份:2011
- 资助金额:
$ 40.5万 - 项目类别:
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