Mechanisms of PCP signaling in axon guidance and cochlear innervation

PCP信号在轴突引导和耳蜗神经支配中的机制

基本信息

  • 批准号:
    10430177
  • 负责人:
  • 金额:
    $ 44.29万
  • 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

项目摘要

Project Summary The cochlea is innervated by spiral ganglion neurons, which relay sound information from sensory hair cells to central auditory targets. Deafness due to acoustic trauma is associated with pathologies in both spiral ganglion neurons and the hair cells which they innervate, and an important aspect of repairing the deafened cochlea is coaxing spiral ganglion neurons to re-innervate their hair cell partners. It is generally anticipated that hair cell re- innervation will require the reactivation of developmental mechanisms. Therefore, understanding early developmental events is an important prerequisite for regeneration-based therapeutic strategies. A subset of spiral ganglion neurons has nociceptive characteristics and are thus equipped to detect acoustic trauma, which may be important for preserving function. These are the type II spiral ganglion neurons, which constitute a minority of cochlear afferents but innervate all outer hair cells. The development of type II neurons is unique and facilitates outer hair cell innervation because their peripheral axons project beyond the inner hair cells. An important component of cochlear innervation is how the type II spiral ganglion neurons subsequently make a distinct 90° turn towards the cochlear base to synapse with multiple outer hair cells. While many aspects of outer hair cell innervation are unknown, our laboratories have found that two signaling pathways, planar cell polarity (PCP) signaling and Eph/Ephrin signaling, are required for the 90° turn that directs the peripheral axon towards the cochlear base. A similar phenotype occurs with loss of the transcription factor Prox1 suggesting that a regulatory hierarchy controls cochlear innervation. The goal of this research is to establish the relationship between these two signaling pathways by examining each in detail and relative to each other. This includes experiments in Aim 1 to distinguish between alternative mechanisms in which PCP proteins pattern the organ of Corti prior to innervation or signal directly to the growth cone. Since the Ephrin receptor EphA7 is also required for axon turning, in Aim 2 we will determine if these pathways are linearly organized or if they are parallel and redundant signals with each promoting turning. Remarkably the EphA7 promoter contains putative Prox1 binding sites suggesting that these guidance mechanisms may be transcriptionally regulated. This hypothesis will be tested further in Aim 3. While these experiments are focused on developmental processes, we anticipate that these are events which must be reenacted during hair cell re-innervation and repair, and therefore the proposed research will advance therapies for repairing the deafened cochlea.
项目总结

项目成果

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MICHAEL R DEANS其他文献

MICHAEL R DEANS的其他文献

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{{ truncateString('MICHAEL R DEANS', 18)}}的其他基金

Mechanisms of PCP signaling in axon guidance and cochlear innervation
PCP信号在轴突引导和耳蜗神经支配中的机制
  • 批准号:
    10207584
  • 财政年份:
    2020
  • 资助金额:
    $ 44.29万
  • 项目类别:
Mechanisms of PCP signaling in axon guidance and cochlear innervation
PCP信号在轴突引导和耳蜗神经支配中的机制
  • 批准号:
    10667459
  • 财政年份:
    2020
  • 资助金额:
    $ 44.29万
  • 项目类别:
Genetic Dissection of Vangl2-Dependent Axon Guidance in the Developing Cochlea
发育中耳蜗中 Vangl2 依赖的轴突引导的遗传解剖
  • 批准号:
    9385989
  • 财政年份:
    2017
  • 资助金额:
    $ 44.29万
  • 项目类别:
Planar Polarity Mechanisms in Mammalian Inner Ear Development
哺乳动物内耳发育中的平面极性机制
  • 批准号:
    8478966
  • 财政年份:
    2013
  • 资助金额:
    $ 44.29万
  • 项目类别:
Planar Polarity Mechanisms in Mammalian Inner Ear Development
哺乳动物内耳发育中的平面极性机制
  • 批准号:
    8819439
  • 财政年份:
    2013
  • 资助金额:
    $ 44.29万
  • 项目类别:
Planar Polarity Mechanisms in Mammalian Inner Ear Development
哺乳动物内耳发育中的平面极性机制
  • 批准号:
    8768685
  • 财政年份:
    2013
  • 资助金额:
    $ 44.29万
  • 项目类别:
Planar Polarity Mechanisms in Mammalian Inner Ear Development
哺乳动物内耳发育中的平面极性机制
  • 批准号:
    10307536
  • 财政年份:
    2013
  • 资助金额:
    $ 44.29万
  • 项目类别:
Planar Polarity Mechanisms in Mammalian Inner Ear Development
哺乳动物内耳发育中的平面极性机制
  • 批准号:
    10531238
  • 财政年份:
    2013
  • 资助金额:
    $ 44.29万
  • 项目类别:
Planar Polarity Mechanisms in Mammalian Inner Ear Development
哺乳动物内耳发育中的平面极性机制
  • 批准号:
    8641337
  • 财政年份:
    2013
  • 资助金额:
    $ 44.29万
  • 项目类别:
Planar Polarity Mechanisms in Mammalian Inner Ear Development
哺乳动物内耳发育中的平面极性机制
  • 批准号:
    10063822
  • 财政年份:
    2013
  • 资助金额:
    $ 44.29万
  • 项目类别:

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