Role of the cardiac cytoskeleton in mRNA localization and hypertrophy
心脏细胞骨架在 mRNA 定位和肥大中的作用
基本信息
- 批准号:10582513
- 负责人:
- 金额:$ 6.72万
- 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:2021-06-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsActive Biological TransportAdultAffectBiologicalBloodCalciumCardiacCardiac MyocytesCell physiologyCellsCessation of lifeChronicComplexCoupledCytoskeletonDataDependenceDepositionDiffusionDiseaseElementsExerciseGeneticGoalsGrowthHealthHealth Care CostsHeartHeart DiseasesHeart HypertrophyHeart failureHumanHypertrophyIn VitroIndividualKineticsKnowledgeLocationMaintenanceMechanicsMessenger RNAMicroscopyMicrotubule-Associated ProteinsMicrotubulesModelingMolecularMotorMuscle CellsMyosin ATPaseNeonatalOxygenPathologicPharmacologyPhysiologicalPlayPost-Translational Protein ProcessingPregnancyProcessProteinsPumpRattusReagentRegulationResearchResearch ProposalsResolutionRibosomal ProteinsRibosomesRoleSarcomeresSiteStressStructureSystemTestingTherapeuticTranscriptTranslatingTranslationsUnited StatesVisualizationWorkbasecell growthcell typecostheart functionhemodynamicsimprovedin vivoin vivo Modelmouse modelnew growthprotein degradationprotein expressionprotein functionresponsespatiotemporaltooltrafficking
项目摘要
PROJECT SUMMARY
In the adult heart, remodeling in response to changing hemodynamic demands occurs primarily through
hypertrophy, the addition of new sarcomeres to individual cardiomyocytes. Physiological hypertrophy, triggered
by pregnancy or exercise, maintains normal organization of cardiac structure and can improve cardiac function.
Pathological hypertrophy, however, often precedes heart failure. This can induce drastic changes to the
cardiomyocyte cytoskeleton. However, with the exception of cellular mechanics, the role of the cardiomyocyte
cytoskeleton in both health and disease has remained understudied.
Recent data suggest that both the actinomyosin and microtubule network may play a role in mRNA and
ribosomal localization in cardiomyocytes, though the mechanism remains unknown. In non-muscle cell types,
actin-based and microtubule-based directed mRNA transport is well characterized. Additionally, myosin and
other sarcomeric mRNAs, ribosomes, and protein degradation machinery appear to localize to the sarcomere
in the cardiomyocyte, supporting a model of local translation for sarcomere maintenance and/or de novo
formation. But how these new sarcomeres are formed remains particularly unclear, and the dependence of
hypertrophy on proper mRNA transport and localization is unknown. The goal of my research proposal is to
determine the relationship between mRNA localization and cardiac hypertrophy both in health and disease. My
preliminary data establishes that the microtubule network is essential for mRNA localization in the rat
cardiomyocyte in vivo and in vitro. To determine the specific mechanism of mRNA transport, I will utilize
pharmacological reagents to destabilize the actin network and specifically inhibit motor proteins in isolated
adult rat cardiomyocytes to test if mRNA localization changes. I will also use the MS2-MCP system to live track
single mRNA transcripts to unambiguously define the mode of mRNA transport. I will leverage molecular
biological tools to mislocalize specific sarcomeric transcripts and to visualize sites of new sarcomere deposition
in growth-responsive neonatal rat cardiomyocytes to test if mRNA sublocalization is required for cardiac
hypertrophy. Finally, I will evaluate if hypertrophy disrupts proper mRNA localization, and if so, dissect the
relative contribution of pathophysiological microtubule network changes to this mislocalization using both in
vitro and in vivo models of hypertrophy. Taken together, the proposed research will definitively establish the
mechanism of mRNA transport and localization in the cardiomyocyte and its function in cardiac hypertrophy.
项目总结
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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Emily A Scarborough其他文献
Emily A Scarborough的其他文献
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{{ truncateString('Emily A Scarborough', 18)}}的其他基金
Role of the cardiac cytoskeleton in mRNA localization and hypertrophy
心脏细胞骨架在 mRNA 定位和肥大中的作用
- 批准号:
10230913 - 财政年份:2021
- 资助金额:
$ 6.72万 - 项目类别: