Dynamic interaction among proteins in hair cells
毛细胞中蛋白质之间的动态相互作用
基本信息
- 批准号:9527906
- 负责人:
- 金额:$ 49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-03-01 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcousticsAdhesivesAffectAgeAllelesAnatomyAuditoryAuditory PhysiologyBehaviorBindingBinding ProteinsBiochemistryBiologicalBiophysicsCDH23 geneCRISPR/Cas technologyCalmodulinCell ShapeCellsCellular MorphologyCellular StructuresCellular biologyCentrosomeCochleaCodeComplexCytoplasmic ProteinDataDevelopmentDimensionsElectrophysiology (science)Epithelial CellsExcisionFoundationsFutureGFI1 geneGene MutationGenesGenomicsGoalsHair CellsHearingHumanImmunohistochemistryImpairmentIn VitroIndividualInheritedKnock-in MouseKnock-outKnockout MiceKnowledgeLabyrinthLacZ GenesLinkMaintenanceMapsMass Spectrum AnalysisMediatingMethodsMicrotubule-Associated ProteinsMicrotubulesMinus End of the MicrotubuleMolecularMolecular BiologyMorphogenesisMusMutationNamesNeuraxisNeuronsOrganOrgan of CortiOuter Hair CellsPathologyPathway interactionsPatientsPatternPeripheralPharmacological TreatmentPhysiologicalPhysiologyPigmentation physiologic functionPillar CellPlayProtein IsoformsProteinsProteomicsReflex actionRegulationReporterReporter GenesRoleSensory DisordersSignal TransductionSpectrinSteelStructureSupporting CellSystemTestingTherapeuticTransport VesiclesUsher SyndromeVesicle Transport PathwayWD RepeatWaardenburg syndromecell typedeafnessdesignexperimental studyexternal ear auriclegene therapyhearing impairmentin vitro Assayin vivomouse modelmutantmutant mouse modelnegative affectnoveloperationpolarized cellpreventsoundspiral ganglion
项目摘要
PROJECT SUMMARY
The cochlea converts sound waves into electrical signals to convey information to the central nervous
system. Highly specialized cells including hair cells, supporting cells and spiral ganglion neurons mediate this
operation. Because complex and sophisticated microtubule (MT) networks are needed for the individualized
cell shapes and structures required for peripheral signal coding, uncovering the protein networks that modulate
MT organization will enrich our understanding of both normal and impaired cochlear physiology. The goal of
this proposal is to investigate three largely unexplored proteins, whose functions may be important for the
regulation of MTs in the inner ear: CAMSAP3, CDH23-C, and WDR47. CAMSAP3 is a MT minus-end binding
protein, while CDH23-C, a cytoplasmic isoform of CDH23, and WDR47, a protein of unknown function, both
interact with CAMSAP3. Deletion or mutation of these genes is linked to hearing impairment in humans and in
mouse models. Thus, they may potentially be responsible for causing hereditary hearing loss. In AIM I, we
investigate the role of CAMSAP3 using conditional knockout mouse models that lack CAMSAP3 in individual
cell types in the cochlea including hair cells, supporting cells, and spiral ganglion neurons. We will examine
these mice using various anatomical and physiological methods to determine the function of CAMSAP3 in
hearing. In AIM II, we investigate the functional consequences of impaired interaction between CDH23-C and
CAMSAP3. We will generate a CDH23-C mutant mouse model that mimics the human Usher Syndrome 1D
mutation that negatively affects this interaction, and evaluate the importance of the role of CDH23-C in MT
regulation via its interaction with CAMSAP3. The experiments are designed to reveal a novel molecular
mechanism that involves MT modulation in the cochlea and that is implicated in Usher Syndrome 1D. In Aim
III, we investigate the function of WDR47 in hearing through both in vivo and in vitro approaches. We will
determine the detailed expression patterns of WDR47 in the cochlea and investigate WDR47's contribution to
hearing using WDR47 knockout mice. We will also dissect the molecular basis of interactions between WDR47
and CAMSAP3, and uncover WDR47-associated proteins through both biochemistry and proteomics. Taken
together, the proposed studies aim to provide critical information regarding the protein networks that regulate
MT organization in the cochlea by focusing on three proteins. Our comprehensive approach utilizes a variety of
methods including molecular and cell biology, biophysics, electrophysiology, in vivo physiology and mass
spectrometry, thereby allowing us to achieve our goals. The data obtained from the proposed experiments will
provide new knowledge about the molecular mechanisms underlying the pathology of hearing loss, and enrich
our understanding of the protein networks important for hearing and deafness. This information will guide our
current and future efforts in directing treatments and/or in preventing hearing loss.
项目摘要
耳蜗将声波转换成电信号,将信息传递给中枢神经
系统高度特化的细胞包括毛细胞、支持细胞和螺旋神经节神经元介导了这一过程
操作由于个体化需要复杂和精密的微管(MT)网络,
细胞的形状和结构所需的外周信号编码,揭示蛋白质网络,调节
MT组织将丰富我们对正常和受损耳蜗生理的理解。的目标
这项建议是研究三种基本上未被探索的蛋白质,它们的功能可能对人类的免疫系统很重要。
内耳中MT的调节:CAMSAP 3、CDH 23-C和WDR 47。CAMSAP 3是一个MT负端结合蛋白
蛋白,而CDH 23-C,CDH 23的细胞质同种型,和WDR 47,一种功能未知的蛋白,
与CAMSAP 3交互。这些基因的缺失或突变与人类的听力障碍有关,
小鼠模型。因此,它们可能是导致遗传性听力损失的潜在原因。在AIM I中,我们
使用缺乏CAMSAP 3的条件性敲除小鼠模型研究CAMSAP 3在个体中的作用。
耳蜗中的细胞类型包括毛细胞、支持细胞和螺旋神经节神经元。我们将研究
这些小鼠使用各种解剖学和生理学方法来确定CAMSAP 3在
听证会在AIM II中,我们研究了CDH 23-C和CDH 23-C之间相互作用受损的功能后果。
CAMSAP 3.我们将产生一个CDH 23-C突变小鼠模型,模拟人类Usher综合征1D
突变的负面影响这种相互作用,并评估的重要性,作用的CDH 23-C在MT
通过与CAMSAP 3的相互作用进行调节。这些实验旨在揭示一种新的分子
这种机制涉及耳蜗中的MT调节,并与Usher综合征1D有关。在Aim中
第三,我们通过体内和体外两种方法研究了WDR 47在听力中的功能。我们将
确定WDR 47在耳蜗中的详细表达模式,并研究WDR 47对
使用WDR 47敲除小鼠进行听力测试。我们还将剖析WDR 47之间相互作用的分子基础。
和CAMSAP 3,并通过生物化学和蛋白质组学揭示WDR 47相关蛋白。采取
总之,拟议的研究旨在提供有关调节蛋白质网络的关键信息,
MT组织在耳蜗通过专注于三种蛋白质。我们的综合方法利用各种
方法包括分子和细胞生物学、生物物理学、电生理学、体内生理学和质量
光谱,从而使我们能够实现我们的目标。从拟议的实验中获得的数据将
提供有关听力损失病理学基础的分子机制的新知识,并丰富
我们对蛋白质网络的理解对听力和耳聋很重要。这些信息将指导我们的
当前和未来在指导治疗和/或预防听力损失方面的努力。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Jing Zheng', 18)}}的其他基金
DYNAMIC INTERATION AMONG PROTEINS IN HAIR CELLS
毛细胞中蛋白质之间的动态相互作用
- 批准号:
8297956 - 财政年份:2012
- 资助金额:
$ 49万 - 项目类别:
DYNAMIC INTERATION AMONG PROTEINS IN HAIR CELLS
毛细胞中蛋白质之间的动态相互作用
- 批准号:
8620644 - 财政年份:2012
- 资助金额:
$ 49万 - 项目类别:
DYNAMIC INTERATION AMONG PROTEINS IN HAIR CELLS
毛细胞中蛋白质之间的动态相互作用
- 批准号:
8431347 - 财政年份:2012
- 资助金额:
$ 49万 - 项目类别:
DYNAMIC INTERATION AMONG PROTEINS IN HAIR CELLS
毛细胞中蛋白质之间的动态相互作用
- 批准号:
9022461 - 财政年份:2012
- 资助金额:
$ 49万 - 项目类别:
Preventing hair cell loss by regulating prestin's function
通过调节 prestin 的功能来防止毛细胞损失
- 批准号:
7933797 - 财政年份:2009
- 资助金额:
$ 49万 - 项目类别:
Preventing hair cell loss by regulating prestin's function
通过调节 prestin 的功能来防止毛细胞损失
- 批准号:
7827241 - 财政年份:2009
- 资助金额:
$ 49万 - 项目类别:
Investigating the nature of prestin-associated proteins
研究 prestin 相关蛋白的性质
- 批准号:
7211417 - 财政年份:2005
- 资助金额:
$ 49万 - 项目类别:
Investigating the nature of prestin-associated proteins
研究 prestin 相关蛋白的性质
- 批准号:
7020704 - 财政年份:2005
- 资助金额:
$ 49万 - 项目类别:
Investigating the nature of prestin-associated proteins
研究 prestin 相关蛋白的性质
- 批准号:
6923414 - 财政年份:2005
- 资助金额:
$ 49万 - 项目类别:
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