Molecular Mechanisms of Hair Bundle Development and Maintenance
发束发育和维护的分子机制
基本信息
- 批准号:10643931
- 负责人:
- 金额:$ 39.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseATPase DomainAccelerationActinsAffectAnimalsArchitectureAuditoryBindingBiochemicalBiological AssayC-terminalCellsClustered Regularly Interspaced Short Palindromic RepeatsCochleaComplexCritical PathwaysCryoelectron MicroscopyCytoskeletonDataDefectDetectionDevelopmentEarElectron MicroscopyEpidermal Growth Factor Receptor Pathway Substrate 8FilamentFluorescence MicroscopyFoundationsGNAI3 geneGPSM2 geneGenesGeneticGenetic EngineeringGoalsGrowthHairHair CellsHearingHeartHeightHumanIn VitroIndividualInheritedLaboratoriesLabyrinthLifeLife Cycle StagesLongevityMaintenanceMeasuresMechanicsMicrofilamentsMicroscopyMolecularMolecular MotorsMotorMusMutant Strains MiceMutationMyosin ATPaseN-terminalOrganellesOutcomePathologicPathologyPathway interactionsPatientsPhasePolymersProcessPropertyProtein IsoformsProteinsPyrenesResolutionSensorySpectrum AnalysisStereociliumStructureTailTestingWHRN geneWorkdeafnessdisabilityexperimental studyhearing impairmenthereditary hearing lossin vitro activityin vivolight microscopymechanotransductionmonomermouse modelmutantnovelparticlepolymerizationpostnatalpreservationprotein complexprotein purificationsingle moleculesoundsynergismtrafficking
项目摘要
Project Summary
The detection of sound in the cochlea requires hair cells and their mechano-sensitive organelles, called
stereocilia. The long-term goal of this laboratory is to study how stereocilia grow and how their integrity is
maintained over a lifetime. These are critical processes and are commonly disrupted in hereditary forms of
human hearing loss. In this proposal, we investigate a molecular motor called myosin 15 (MYO15A) that sets
the size of the actin filament core that is the structural foundation within each stereocilium. Mutations in the
MYO15A gene cause human hereditary hearing loss, DFNB3. Our initial experiments have revealed a novel
mechanism that allows MYO15A to control the actin core, and we hypothesize that the hair cell regulates
stereocilia architecture using different MYO15A isoforms. To test this, we will investigate the molecular properties
of MYO15A to understand how it influences growth of the actin core, reveal how these activities are regulated
within the hair cell, and examine how mutations cause hearing loss in a mouse model. In Aim 1, we use purified
proteins and spectroscopy / single-molecule assays to extensively characterize how MYO15A accelerates actin
polymerization. As part of this, we will introduce mutations to explore candidate regions within MYO15A that
underlie this activity. In Aim 2, we expand our study to different isoforms of MYO15A and use biochemical assays
and cryo-electron microscopy to investigate key differences in their enzymatic activity and how these are
regulated. In Aim 3, we characterize a mutant mouse where a novel MYO15A isoform has been removed using
CRISPR genetic engineering, and study how these animals lose their hearing using a combination of high-
resolution electron and light microscopy. Overall, our proposal will provide critical new information into basic
mechanisms of stereocilia plasticity, in addition to revealing the distinct pathologies that cause deafness in
patients suffering with DFNB3.
项目总结
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The actin cytoskeleton in hair bundle development and hearing loss.
- DOI:10.1016/j.heares.2023.108817
- 发表时间:2023-09-01
- 期刊:
- 影响因子:2.8
- 作者:Park, Jinho;Bird, Jonathan E.
- 通讯作者:Bird, Jonathan E.
The ATPase mechanism of myosin 15, the molecular motor mutated in DFNB3 human deafness.
- DOI:10.1074/jbc.ra120.014903
- 发表时间:2021-01
- 期刊:
- 影响因子:0
- 作者:Jiang F;Takagi Y;Shams A;Heissler SM;Friedman TB;Sellers JR;Bird JE
- 通讯作者:Bird JE
Myosin motors in sensory hair bundle assembly.
- DOI:10.1016/j.ceb.2022.102132
- 发表时间:2022-12
- 期刊:
- 影响因子:7.5
- 作者:Moreland, Zane G.;Bird, Jonathan E.
- 通讯作者:Bird, Jonathan E.
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Jonathan Edward Bird其他文献
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{{ truncateString('Jonathan Edward Bird', 18)}}的其他基金
Molecular Mechanisms of Hair Bundle Development and Maintenance
发束发育和维护的分子机制
- 批准号:
10029316 - 财政年份:2020
- 资助金额:
$ 39.38万 - 项目类别:
Molecular Mechanisms of Hair Bundle Development and Maintenance
发束发育和维护的分子机制
- 批准号:
10434026 - 财政年份:2020
- 资助金额:
$ 39.38万 - 项目类别:
Molecular Mechanisms of Hair Bundle Development and Maintenance
发束发育和维护的分子机制
- 批准号:
10205022 - 财政年份:2020
- 资助金额:
$ 39.38万 - 项目类别:
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