Neuron-Glia Interactions in the Cochlea
耳蜗中神经元-神经胶质细胞的相互作用
基本信息
- 批准号:10417731
- 负责人:
- 金额:$ 53.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AcuteAffectAgeAuditoryAxonBehaviorBrainCellsCochleaConnective TissueCuesCytoskeletonDataDetectionDevelopmentDiphtheria ToxinDiseaseEmbryoEmbryonic DevelopmentEventFamilyFreezingGATA2 transcription factorGATA3 geneGene ExpressionGenesGeneticGlial DifferentiationGlioblastomaGoalsHair CellsHearingHumanImageIn Situ HybridizationIndividualInstructionIonsKnockout MiceKnowledgeLabelLabyrinthLearningLightMediatingMolecularMolecular GeneticsMorphologyMouse StrainsMovementMusMutant Strains MiceMutateMutationNatural regenerationNeural CrestNeural Crest CellNeuraxisNeuritesNeurogliaNeuronsNoiseOrgan of CortiPatternPeripheralPeripheral Nervous SystemPhenotypePlayPopulationProcessPrognosisPropertyPublishingRadialReportingRoleSchwann CellsSensorineural Hearing LossShapesSignal TransductionSourceSupporting CellSyndromeSystemTestingTimeTissuesToxinViralalpha Toxinbasecell typecochlear developmentconditional knockoutexperienceexperimental studyfollow-upgenetic approachglial cell developmenthearing impairmenthereditary hearing lossin vivoinsightmutantmyelinationnerve supplyneuron developmentneuron lossotoconiapreventprogenitorprogramsprogressive hearing lossrepairedsingle-cell RNA sequencingsomatosensorysoundspiral ganglionstem-like celltime usetranscription factortransmission process
项目摘要
Project Summary
In this project, we will investigate the cellular and molecular events that allow cochlear glia to shape and sustain
auditory circuits for a lifetime of hearing. Like the other glia of the peripheral nervous system, cochlear glia
develop from the neural crest, a highly migratory and plastic population of progenitors that produce neurons and
connective tissue as well as satellite glia and Schwann cells. Despite their common origin with other peripheral
glia, the glia that ultimately populate the cochlea take on some unique properties that are essential for the sense
of hearing, such as the ability to myelinate spiral ganglion neuron (SGNs) cell bodies. In addition, cochlear glia
provide crucial trophic support for the highly active SGNs and also clear away excess ions and transmitter that
could otherwise be damaging. Finally, whereas glial precursors generally migrate along axons, in the cochlea,
the glial precursors migrate ahead of the SGN neurites and appear to facilitate efficient formation of orderly radial
bundles along the tonotopic axis. Our overall goal is to learn how cochlear glia acquire these properties. Based
on data from our lab and others, we hypothesize that the transcription factors Gata2 and Gata3 act separately
in developing glia and SGNs to coordinate interactions needed for cochlear wiring and function. In support of
this idea, we found that Gata2 is expressed by cochlear glia but not by glia of the somatosensory system.
Additionally, previous analysis of Gata2 mutant mice revealed hearing deficits and SGN loss that could be due
to unrecognized effects on the glia. On the other hand, we observed that Gata3 mutant SGNs extend their
neurites as if they are unable to interact with the glia, resulting in disorderly wiring that mimics what occurs when
glia are depleted from the developing cochlea. We will follow up on these observations by using molecular
genetic approaches in the mouse to characterize glial organization and its effects on SGN neurite outgrowth
(Aim 1), to determine the role of Gata2 in cochlear glia development (Aim 2), and to compare GATA-dependent
programs of gene expression in SGNs and glia (Aim 3). For Aim 1, we will use genetic and viral approaches to
visualize glia and disrupt their ability to interact with developing SGN neurites, as assessed in fixed tissue and
by time-lapse imaging. For Aim 2, we will delete Gata2 from cochlear glia and assess effects on cochlear wiring,
on glial differentiation and function, on SGN survival, and on auditory function, as assessed by recording ABRs
and DPOAEs. For Aim 3, we will perform scRNA-sequencing of embryonic Gata2 and Gata3 mutant cochleas,
both to identify downstream genes that may mediate neuron-glia interactions and to learn how neurons and glia
are affected by each other during development. Together, these studies will advance our knowledge of cochlear
glia development and function, with direct implications for hearing loss, including that associated with Gata2
(Emberger Syndrome) and Gata3 (HDR Syndrome) mutations in humans.
项目摘要
在这个项目中,我们将调查的细胞和分子事件,使耳蜗胶质细胞的形状和维持
听觉回路来维持一生的听觉。与周围神经系统的其他胶质细胞一样,耳蜗胶质细胞
从神经嵴发展而来,神经嵴是一种高度迁移和可塑的祖细胞群体,产生神经元,
结缔组织以及卫星胶质细胞和雪旺细胞。尽管它们与其他周边国家有着共同的起源,
神经胶质细胞,神经胶质细胞,最终填充耳蜗,采取了一些独特的属性,是必不可少的感觉
听觉,如螺旋神经节神经元(SGN)细胞体髓鞘化的能力。此外,耳蜗神经胶质
为高度活跃的SGN提供重要的营养支持,并清除多余的离子和递质,
否则会造成破坏最后,尽管神经胶质前体通常沿着轴突迁移,但在耳蜗中,
胶质细胞前体迁移到SGN神经突的前面,似乎有助于有效形成有序的放射状突起。
沿着音调拓扑轴成束。我们的总体目标是了解耳蜗神经胶质细胞如何获得这些特性。基于
根据我们实验室和其他实验室的数据,我们假设转录因子Gata 2和Gata 3分别起作用,
在发展神经胶质和SGN,以协调耳蜗布线和功能所需的相互作用。支持
基于这一想法,我们发现Gata 2在耳蜗神经胶质细胞中表达,而在躯体感觉系统的神经胶质细胞中不表达。
此外,先前对Gata 2突变小鼠的分析显示,听力缺陷和SGN丧失可能是由于
对神经胶质细胞的影响。另一方面,我们观察到Gata 3突变SGN延长了它们的
神经突似乎无法与神经胶质细胞相互作用,导致无序的布线,模仿当神经突被切断时发生的情况。
神经胶质从发育中的耳蜗中耗尽。我们将通过使用分子生物学方法来跟踪这些观察结果。
遗传学方法在小鼠中表征胶质组织及其对SGN神经突生长的影响
(Aim 1),确定Gata 2在耳蜗神经胶质细胞发育中的作用(目的2),并比较GATA依赖的
SGN和神经胶质细胞中基因表达的程序(Aim 3)。对于目标1,我们将使用遗传和病毒方法,
可视化胶质细胞并破坏其与发育中的SGN神经突相互作用的能力,如在固定组织中评估的那样,
通过延时成像。对于目标2,我们将从耳蜗神经胶质细胞中删除Gata 2,并评估对耳蜗布线的影响,
对胶质细胞分化和功能、SGN存活和听觉功能的影响,通过记录ABR进行评估
和DPOAE。对于目标3,我们将对胚胎Gata 2和Gata 3突变耳蜗进行scRNA测序,
既要确定可能介导神经元-神经胶质相互作用的下游基因,
在发展过程中相互影响。总之,这些研究将促进我们对耳蜗的了解。
神经胶质细胞的发育和功能,与听力损失有直接关系,包括与Gata 2相关的听力损失
(Emberger综合征)和Gata 3(HDR综合征)突变。
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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Lisa Goodrich其他文献
Lisa Goodrich的其他文献
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{{ truncateString('Lisa Goodrich', 18)}}的其他基金
A novel mechanism for synapse localization in the retina
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$ 53.53万 - 项目类别:
A novel mechanism for synapse localization in the retina
视网膜突触定位的新机制
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10152981 - 财政年份:2020
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$ 53.53万 - 项目类别:
Non-sensory cells as a potential source for signaling molecules in the cochlea
非感觉细胞作为耳蜗信号分子的潜在来源
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9127473 - 财政年份:2016
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Afferent-efferent interactions in the developing cochlea
发育中的耳蜗中的传入-传出相互作用
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10062939 - 财政年份:2016
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Afferent-efferent interactions in the developing cochlea
发育中的耳蜗中的传入-传出相互作用
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9261880 - 财政年份:2016
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$ 53.53万 - 项目类别:
Molecular control of neuronal shape and connectivity in the developing retina
视网膜发育中神经元形状和连接的分子控制
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8353135 - 财政年份:2012
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$ 53.53万 - 项目类别:
The role of Fat3 in amacrine cell dendrite development.
Fat3 在无长突细胞树突发育中的作用。
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8511674 - 财政年份:2012
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