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(由适用提供):在使用诱导多能干细胞衍生的心肌细胞(IPSC-CM)方面,已经大幅提高了对可遗传人类遗传性心脏病的研究。尽管这些进步最终将导致新的治疗选择和改善患者咨询,但这些细胞模型系统还允许机械洞察力,并为对人类心脏组织进行建模提供了平台。后者至关重要,因为心肌病(遗传和非遗传形式)或心力衰竭经常经历心律不齐,可能导致猝死。为了研究遗传疾病综合征引起心律不齐的易感性,由我们的团队开发的工程心脏切片(EHS)将培养IPSC-CMS,该团队概括了天然的3D微环境,并启用了细胞和细胞外矩阵之间的机电相互作用。我们的EHS支持雕刻的IPSC-CMS的增长;为细胞提供重要的拓扑,生化和机械信号;明显的功能组织行为,包括协调的电生理和收缩活性;并可以以可量化的方式维持心律不齐。在这个项目中,我们建议使用EHS研究心律不齐的表现和进展的机制,从而促进猝死。作为对心律不齐进行建模的遗传工具,我们将研究从心律失常右心室发育不良/心肌病(ARVC)产生的IPSC,这些问题影响心脏脱粒的蛋白质。在患者中,这种疾病具有高度的心律失常,可能导致年轻运动员突然心脏死亡。因此,该项目的目的是研究结构缺陷如何促进EHS的心律不齐。具体而言,我们将确定1)在AC的早期隐藏阶段起作用,以损害细胞间的机械耦合,从而导致异常电耦合,电导导导导导导导导导导导导导导感和再渗透性异常,并导致钠通道的二级变化,也会导致钠的变化速度,并导致slost inder nyder proctions nyder nyder nyder nyder nyder nyder nyder nyder hyder nyder and andy,则在AC的早期隐藏阶段起作用。该项目涉及三个完整且相关的目标。 AIM 1将研究同步相互作用和组织微环境对ARVC IPSC-CMS疾病表型的表达和进展的重要性。 AIM 2将开发模拟运动模型,以确定ARVC EHS模型中心律不齐的增加风险。 AIM 3将研究ARVC的EHS模型中不同天然,细胞外属性和组织水平心律失常的指导性提示。这项研究的结果将阐明心律不齐的机制和与机械连接异常相关的心脏猝死,不仅在ARVC中运作,而且还以其他更常见的心肌病形式起作用。我们在心肌细胞中有关组织微环境和疾病进展的研究是迈向鉴定原发性和辅助性心律失常疾病途径的关键一步,这对于开发旨在治疗可遗传心脏疾病的新疗法可能是无价的。
项目成果
期刊论文数量(0)
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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
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- 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
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- 批准号:
10593334 - 财政年份:2020
- 资助金额:
$ 40.5万 - 项目类别:
Engineered Human Heart Slice for Testing Drug-Induced Arrhythmia
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Mechanoelectrical Interactions Between Cardiac Myofibroblasts and Myocytes
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- 批准号:
9204715 - 财政年份:2016
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$ 40.5万 - 项目类别:
ARVD/C Dysfunction in Human Stem Cell-Derived Cardiac Tissue
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- 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:
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