Engineered Stem Cells for Cardiac Repair
Engineered Stem Cells for Cardiac Repair
批准号:
10078963
负责人:
Charles E Murry
金额:
$66.56万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-02-01 至 2022-03-31
关键词:
ATP Synthesis PathwayATP phosphohydrolaseActinsAcute myocardial infarctionAdultAffectAftercareAnimalsBindingBiochemicalCRISPR/Cas technologyCanis familiarisCardiacCardiac MyocytesCardiotonic AgentsCell LineCell SurvivalCell TherapyCell TransplantationCellsCellular Metabolic ProcessChronicCicatrixContractsCost efficiencyCoupledDataDegradation PathwayDependovirusDepressed moodDevicesDrug Delivery SystemsEchocardiographyEngineeringEnzymesEquilibriumFamily suidaeFeedbackGap JunctionsGene TargetingGoalsHeartHeart TransplantationHeart failureHip region structureHumanHuman EngineeringImmunocompromised HostIn VitroInfarctionIschemiaLeftLeft Ventricular FunctionLongevityMacaca nemestrinaMagnetic Resonance ImagingMeasurementMediatingMitochondriaMitoticModelingModificationMusMuscleMuscle CellsMuscle ContractionMutationMyocardialMyocardial InfarctionMyocardial ReperfusionMyocardiumMyosin ATPaseNatureNucleotidesNude RatsOperative Surgical ProceduresPathway interactionsPerformancePhosphocreatinePhosphorylationPhosphotransferasesPhysiologicalPower strokeProductionProteinsPumpRattusRecoveryRelaxationReperfusion InjuryRespirationRestRibonucleotide ReductaseRodentRodent ModelStressStructureTertiary Protein StructureTestingTherapeuticTimeTissuesToxic effectTransgenic OrganismsTransplantationUbiquitinationVariantVentricularVentricular FunctionViral VectorWorkadeno-associated viral vectorbasecardiac repaircell replacement therapycoronary artery occlusiondesignenergy balanceengineered stem cellsexperimental studyexpression vectorgene therapygraft functionheart functionhuman embryonic stem cellhuman stem cellsimprovedimproved functioningimproved outcomein vivoinduced pluripotent stem cellmouse modelnonhuman primatenoveloverexpressionpreventprotein degradationrepair functionrepair strategyresponsesmall moleculestem cellstreatment strategyvector
中文摘要
摘要。这个项目是建立在博士之间多年的合作工作。murray和Regnier
英文摘要
ABSTRACT. This project is built around years of collaborative work between Drs. Murry and Regnier
studying human embryonic stem cell derived cardiomyocytes (hESC-CMs) as a potential cell replacement
strategy for cardiac repair following myocardial infarction (MI). Our group has shown that hESC-CMs and
human inducible pluripotent SC-CMs (hiPS-CMs) can be produced at a scale and purity that permit testing in
rodent models and the animal most likely to predict the human response: the non-human primate (NHP;
Macaca nemestrina). We have demonstrated the ability of these cells to engraft in rodent models, covering the
entire scar, and electrically integrate with host tissue to improve left ventricular performance.
This project is based on two fundamental discoveries: 1) 2-deoxy ATP (dATP) is a potent natural
nucleotide stimulant of cardiac contractility (via improved myosin binding to actin & faster detachment after the
power stroke), and 2) hiPSC-CMs that overexpress the rate-limiting enzyme for dATP synthesis, ribonucleotide
reductase (RNR), have both increased contractility and deliver dATP to the rest of the heart via gap junctions.
Thus we will test the hypothesis that engineering hiPSC-CMs to elevate RNR (RNR-hiPSC-CMs) will improve
outcomes in cell replacement therapy for MI (compared with control hiPSC-CMs), improving contractility of
both graft and native myocardium. There are several highly novel aspects to our approach. 1) It is the first
proposed use of cellular nucleotide manipulation to improve in vivo cardiac function. 2) The approach is not
limited to replacement of lost tissue (with hiPSC-CMs) with a better functioning graft, but may also substantially
benefit the post-MI depressed function of native myocardium. 3) The first use of engineered hiPSC-CMs to
deliver what is effectively a small molecule therapy (dATP), a natural compound that improves heart muscle
contraction. This effectively makes hiPSC-CMs a drug delivery device with cardiac specific delivery and
effects. Aim 1 will develop and test engineered mutations in RNR that increase it's stability and activity in
cardiomyocytes and their ability to titrate increasing levels of dATP produced in hiPSC-CMs. Aim 2 will use
AAV vectors for RNR variants, selected from Aim 1, to investigate their capacity to improve cardiac function in
a mouse model of myocardial infarct and heart failure. Aim 3 will produce engineered hiPS cell lines that will
act as dATP `donor cells' following differentiation, for transplantation into acute MI and more challenging
chronic MI athymic rat models to determine their capacity to improve function beyond transplantation of non-
engineered hiPSC-CMs. We will evaluate the persistence of these effects and determine the long-term
stability and viability of these cell lines. We expect significant contractile improvement of both the graft and
native myocardium with RNR-hiPSC-CMs vs. hiPSC-CMs and this effect will be modulated by the dATP
producing capacity of the transplanted cells. Results from these studies will elucidate the potential of this
combination cell- and small molecule therapy to ameliorate or even improve pump function in failing hearts.
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会议论文
Function, composition, and mechanism of RNA splicing factories in cardiomyopathy
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批准号:10583011
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项目类别:
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资助金额:$58.66万
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财政年份:2022
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负责人:Charles E Murry
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依托单位:
Metabolic and Transcriptional Reprogramming of Cardiac Maturation
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批准号:10202988
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项目类别:
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资助金额:$61.77万
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财政年份:2021
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负责人:Charles E Murry
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依托单位:
Metabolic and Transcriptional Reprogramming of Cardiac Maturation
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批准号:10579257
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项目类别:
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资助金额:$61.77万
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财政年份:2021
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负责人:Charles E Murry
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依托单位:
Metabolic and Transcriptional Reprogramming of Cardiac Maturation
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批准号:10378094
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项目类别:
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资助金额:$61.77万
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财政年份:2021
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负责人:Charles E Murry
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依托单位:
Mechanisms of Cell-Based Heart Regeneration
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批准号:10371893
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项目类别:
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资助金额:$87.12万
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财政年份:2019
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负责人:Charles E Murry
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依托单位:
Engineered Stem Cells for Cardiac Repair
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批准号:10293039
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项目类别:
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资助金额:$5.4万
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财政年份:2018
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负责人:Charles E Murry
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依托单位:
Engineered Stem Cells for Cardiac Repair
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批准号:10544645
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项目类别:
-
资助金额:$10.7万
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财政年份:2018
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负责人:Charles E Murry
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依托单位:
Primate Heart Regeneration
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批准号:9101271
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项目类别:
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资助金额:$87.13万
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财政年份:2016
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负责人:Charles E Murry
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依托单位:
Primate Heart Regeneration
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批准号:9246569
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项目类别:
-
资助金额:$87.13万
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财政年份:2016
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负责人:Charles E Murry
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依托单位:
Project 4: UW-CNOF Biological Model Development and Data Generation
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批准号:9021415
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项目类别:
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资助金额:$51.16万
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财政年份:2015
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负责人:Charles E Murry
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依托单位:
Cardiac Differentiation from Human Embryonic Stem Cells
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批准号:8460656
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项目类别:
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资助金额:$38.98万
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财政年份:2012
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负责人:Charles E Murry
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依托单位:
STEM CELLS AND CARDIOVASCULAR REPAIR
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批准号:8514343
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项目类别:
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资助金额:$80.34万
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财政年份:2010
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负责人:Charles E Murry
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依托单位:
Vascularization and Growth of Human Myocardial Grafts
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批准号:7806058
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项目类别:
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资助金额:$64.53万
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财政年份:2010
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负责人:Charles E Murry
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依托单位:
STEM CELLS AND CARDIOVASCULAR REPAIR
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批准号:8485640
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项目类别:
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资助金额:$240.8万
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财政年份:2010
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负责人:Charles E Murry
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依托单位:
STEM CELLS AND CARDIOVASCULAR REPAIR
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批准号:8623221
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项目类别:
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资助金额:$79.82万
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财政年份:2010
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负责人:Charles E Murry
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依托单位:
STEM CELLS AND CARDIOVASCULAR REPAIR
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批准号:7762323
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项目类别:
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资助金额:$253.94万
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财政年份:2010
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负责人:Charles E Murry
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依托单位:
STEM CELLS AND CARDIOVASCULAR REPAIR
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批准号:8885402
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项目类别:
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资助金额:$43.26万
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财政年份:2010
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负责人:Charles E Murry
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依托单位:
Administrative Core
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批准号:7806068
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项目类别:
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资助金额:$16.75万
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财政年份:2010
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负责人:Charles E Murry
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依托单位:
STEM CELLS AND CARDIOVASCULAR REPAIR
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批准号:8076344
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项目类别:
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资助金额:$249.08万
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财政年份:2010
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负责人:Charles E Murry
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依托单位:
STEM CELLS AND CARDIOVASCULAR REPAIR
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批准号:8676866
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项目类别:
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资助金额:$247.88万
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财政年份:2010
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负责人:Charles E Murry
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依托单位: