MicroRNA Control of Dilated Cardiomyopathy
MicroRNA 控制扩张型心肌病
基本信息
- 批准号:9173372
- 负责人:
- 金额:$ 60.84万
- 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:2016-06-01 至 2020-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAdrenergic AgentsAffectBiologicalBiological ProcessCalciumCardiacCardiac MyocytesCause of DeathChronicClinicalCodeCollectionContractile ProteinsDataDilated CardiomyopathyDiseaseDisease ProgressionDisease susceptibilityDrug TargetingEquilibriumFunctional disorderGene MutationGeneticGenetic Predisposition to DiseaseGenotypeGoalsHeart DiseasesHeart TransplantationHeart failureHereditary DiseaseHumanIn VitroIndividualKnock-inKnock-in MouseLamininLinkMechanical StimulationMechanicsMediatingMediator of activation proteinMessenger RNAMicroRNAsModelingMusMutationNatureNuclearPathway interactionsPatientsPhenotypePhysiologicalPredispositionProteinsPumpRegulationResearchSERCA2aSarcomeresSarcoplasmic ReticulumSignal TransductionStagingStimulusStressStretchingStructural GenesTechnologyTestingTranslational RepressionTranslationsUntranslated RNAbasebiophysical analysisbiophysical propertiesconnectincostdisease phenotypedisease-causing mutationfamilial dilated cardiomyopathyheart functionhigh throughput screeningimprovedin vivoindividual patientinduced pluripotent stem cellinsightmimeticsmutantnew therapeutic targetpreventprotein expressionprotein functionresponsereuptakescreeningtherapeutic targettranscription factorwhole genome
项目摘要
microRNA Control of Dilated Cardiomyopathy
Dilated cardiomyopathy is a major cause of heart failure and approximately 20-35% of
cases have genetic etiologies. The link between the genetics and disease progression
remains poorly understood, despite being a major focus of current research. microRNAs
have emerged as important regulators of heart disease. Approximately 2000 of these
short, non-coding RNA molecules function in vivo by repressing the stability and
translation of protein-coding mRNAs. miRNAs regulate nearly all biological processes
examined, often by suppressing multiple points in a pathway produce a coherent
biological response to stimuli. We have recently used functional screening of whole
genome collections of synthetic miRNAs to identify miRNAs that suppress
cardiomyocyte contractility in vitro and shown that blocking one of these, miR-25,
improves heart function in a heart failure model (Nature, 2014, doi:10.1038).
We applied high throughput screening to identify miRNAs that regulate the decline in
cardiomyocyte function in familial DCM using patient-specific hiPSCs. Mechanical
strain and chronic adrenergic stimulation induce a number of these miRNAs. Together
our data have revealed that miRNAs connect physiological stress to suppression of
proteins that maintain calcium regulation and sarcomeric integrity.
Here we propose to systematically investigate miRNA control of familial DCM. AIMS 1
and 2 will identify miRNAs that have the potential to suppress contractility in DCM, using
patient hiPSC-cardiomyocytes (cTn-T R173W and R141W) and a mouse DCM model
corresponding to one of the DCM patient hiPSC models (cTn-T R173W); AIM 3 will
determine the proteins that are repressed by the miRNAs to influence disease, and AIM
4 will establish how miRNAs midiate the response to pathological stimuli of increased
wall tension and chronic adrenergic stimulation that contribute to disease progression.
In summary, the research addresses the hypothesis that familial DCM involves
dysregulation of miRNAs that impair Ca2+ handling, contractility and sarcomere integrity.
Elucidating the miRNAs and their protein targets should provide insight into disease
progression and point to novel therapeutic targets.
扩张型心肌病的microRNA调控
扩张型心肌病是心力衰竭的主要原因,大约20%-35%的
这些病例有遗传原因。遗传学与疾病进展之间的联系
尽管是当前研究的主要焦点,但人们对此仍知之甚少。MicroRNAs
已经成为心脏病的重要调节者。其中大约有2000个
短的、非编码的RNA分子在体内通过抑制稳定性和
翻译蛋白质编码的mRNAs。MiRNAs调控几乎所有的生物过程
通常通过抑制一条路径中的多个点来产生相干的
对刺激的生物反应。我们最近使用了全身性功能筛查
合成miRNAs的基因组集合,以识别抑制
心肌细胞的体外收缩能力,并表明阻断其中之一,miR-25,
改善心力衰竭模型的心功能(自然,2014年,DOI:10.1038)。
我们应用高通量筛选来识别调节细胞周期下降的miRNAs。
使用患者特异性HiPSCs的家族性DCM患者的心肌细胞功能。机械式
压力和慢性肾上腺素能刺激诱导了许多这样的miRNAs。同舟共济
我们的数据显示,miRNAs将生理应激与抑制
维持钙调节和肌节完整性的蛋白质。
在这里,我们建议系统地研究miRNA对家族性扩张性心肌病的控制。目标1
和2将确定有可能抑制DCM收缩的miRNAs,使用
病人HiPSC-心肌细胞(cTn-T R173W和R141W)和小鼠DCM模型
对应于DCM患者HiPSC模型之一(cTn-T R173W);AIM 3将
确定被miRNAs抑制以影响疾病的蛋白质,目的
4将确定miRNAs如何调节对病理性刺激增加的反应
导致疾病进展的室壁张力和慢性肾上腺素能刺激。
总而言之,这项研究解决了家族性DCM涉及的假设
MiRNAs的失调,损害了钙离子的处理、收缩和肌节的完整性。
阐明miRNAs及其蛋白靶标有助于深入了解疾病
进展和指向新的治疗靶点。
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(0)
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MARK MERCOLA其他文献
MARK MERCOLA的其他文献
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{{ truncateString('MARK MERCOLA', 18)}}的其他基金
hiPSC Modeling of Restrictive Cardiomyopathy for Drug Testing
用于药物测试的限制性心肌病的 hiPSC 模型
- 批准号:
10716393 - 财政年份:2023
- 资助金额:
$ 60.84万 - 项目类别:
High throughput platform for simultaneous multiparametric assessment of cardiac physiology for heart failure drug development
用于心力衰竭药物开发的心脏生理学同步多参数评估的高通量平台
- 批准号:
10745000 - 财政年份:2023
- 资助金额:
$ 60.84万 - 项目类别:
Targeting the genotype to phenotype link in HCM as a therapeutic strategy
将 HCM 中的基因型与表型联系作为治疗策略
- 批准号:
10355529 - 财政年份:2021
- 资助金额:
$ 60.84万 - 项目类别:
Targeting the genotype to phenotype link in HCM as a therapeutic strategy
将 HCM 中的基因型与表型联系作为治疗策略
- 批准号:
10576285 - 财政年份:2021
- 资助金额:
$ 60.84万 - 项目类别:
Kinetic Imaging Cytometer (KIC) for High Throughput Studies of Cellular Physiology
用于细胞生理学高通量研究的动态成像细胞仪 (KIC)
- 批准号:
10175806 - 财政年份:2021
- 资助金额:
$ 60.84万 - 项目类别:
Single-cell Multi-omic Profiling of Drug Responses Using Pooled iPSC-CM Differentiation
使用汇集 iPSC-CM 分化进行药物反应的单细胞多组学分析
- 批准号:
10671175 - 财政年份:2019
- 资助金额:
$ 60.84万 - 项目类别:
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