Alpha-catenin function in cardiomyocyte adhesion and cytoskeletal organization
α-连环蛋白在心肌细胞粘附和细胞骨架组织中的功能
基本信息
- 批准号:10297260
- 负责人:
- 金额:$ 39.94万
- 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 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:Actin-Binding ProteinActinsAdaptor Signaling ProteinAdherens JunctionAdhesionsAdhesivesAffectAllosteric RegulationArchitectureBindingBiochemicalBiochemistryBiologicalCadherinsCardiac MyocytesCardiomyopathiesCell AdhesionCell CommunicationCell-Cell AdhesionCellsCellular biologyCollectionComplexCouplingCuesCytoskeletal ModelingCytoskeletal ProteinsCytoskeletonDataDesmosomesDevelopmentEpithelialEquilibriumExtracellular MatrixFoundationsGoalsGrantHealthHeartHeart DiseasesHomeostasisHumanIn SituIndividualIntercalated discIntermediate FilamentsKnowledgeLeadLigand BindingLigandsLinkMaintenanceMechanicsMediatingMembraneMicrofilamentsMolecularMutationMyofibrilsOutcomeOutputPeripheralPropertyProteinsProteomicsPublishingResearchRoleSeriesSignal TransductionStructureSystemTestisThermodynamicsTissuesVinculinWorkalpha catenincardiogenesisdesignexperimental studyheart functioninsightlink proteinmechanical forceoperationprotein complexreconstitutionrecruitresponsetooltreatment strategy
项目摘要
Project Summary
With every heartbeat, the junctional complexes that couple cardiomyocytes must transmit the mechanical
forces of contraction while maintaining adhesive homeostasis. Cardiomyocytes are linked end-to-end by the
intercalated disc (ICD), a specialized junction that coordinates cell signaling, electrical and mechanical
operations. The ICD comprises adherens junctions (AJs) and desmosomes that connect the actin and
intermediate filament cytoskeletons, respectively, of adjoining cells. ICD function requires multiple adhesion
and cytoskeletal proteins and mutations in these proteins are linked to cardiomyopathies. However, relatively
little is known about how adhesion complexes are regulated to establish and maintain heart tissue integrity.
The core of the adherens junction is the cadherin-catenin complex, which is connected to the actin
cytoskeleton through a-catenin. a-Catenin is a multifunctional, mechanoresponsive actin-binding protein that
localizes to the cardiomyocyte ICD. However, a-catenin functions in cell-cell adhesion in cardiomyocytes are
poorly understood. Our objective in this application is to determine how mechanical and molecular inputs are
transduced through the two a-catenins expressed in the human heart – aE(Epithelial)-catenin and aT(Testes)-
catenin – to regulate cardiomyocyte adhesion. Our rationale is that defining the individual and collective roles
of a-catenin at cardiomyocyte AJs will provide fundamental insight into how cardiomyocyte AJs balance
mechanical and signaling functions. We hypothesize that aE-catenin and aT-catenin form unique cadherin-
catenin complexes in response to cellular cues to function as mechanical checkpoints for ICD assembly and
cardiomyocyte organization. In this proposal, we seek to: 1) define the allosteric mechanisms that regulate a-
catenin ligand binding at the cardiomyocyte AJ; 2) determine how ligand recruitment to a-catenin promotes AJ
assembly and cytoskeletal attachment; and 3) identify how external mechanical cues regulate AJ organization.
Knowledge to be gained through our studies include a detailed, mechanistic understanding of how a-catenin
molecular properties are tuned for adhesion in cardiomyocytes; how unique molecular complexes are built
along the cardiomyocyte AJ to establish and maintain adhesion; and how external mechanical cues feed into
the cardiomyocyte AJ to drive organization. This comprehensive, multiscale analysis will develop new tools
and acquire new knowledge about the molecular mechanisms of cell adhesion in cardiomyocytes.
Understanding the fundamental mechanisms of cell adhesion in cardiomyocytes is necessary for determining
how mutations in ICD proteins lead to heart disease and inform the development of new strategies for the
treatment of cardiomyopathies.
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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Adam Vincent Kwiatkowski其他文献
Adam Vincent Kwiatkowski的其他文献
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{{ truncateString('Adam Vincent Kwiatkowski', 18)}}的其他基金
Alpha-catenin function in cardiomyocyte adhesion and cytoskeletal organization
α-连环蛋白在心肌细胞粘附和细胞骨架组织中的功能
- 批准号:
10671042 - 财政年份:2016
- 资助金额:
$ 39.94万 - 项目类别:
Alpha-catenin function in cardiomyocyte adhesion and cytoskeletal organization
α-连环蛋白在心肌细胞粘附和细胞骨架组织中的功能
- 批准号:
10470291 - 财政年份:2016
- 资助金额:
$ 39.94万 - 项目类别:
Alpha-catenin function in cardiomyocyte adhesion and cytoskeletal organization
α-连环蛋白在心肌细胞粘附和细胞骨架组织中的功能
- 批准号:
9104366 - 财政年份:2016
- 资助金额:
$ 39.94万 - 项目类别:
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