Molecular mechanisms of auditory nAChR synapse assembly

听觉 nAChR 突触组装的分子机制

基本信息

  • 批准号:
    8519408
  • 负责人:
  • 金额:
    $ 42.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-19 至 2015-08-31
  • 项目状态:
    已结题

项目摘要

Abstract: Sensorineural hearing loss affects 30 million Americans. Aging, noise-overexposure, infection and ototoxic antibiotics all lead to sensory hair cell degeneration and permanent hearing loss. Recently, hair cell regeneration and partial function restoration were induced in the mature mammalian inner ear. However, little is known about molecular mechanisms that direct functional synapse assembly in either normal developing or regenerated hair cells. Our planned studies will define these mechanisms in vivo and identify molecules required for synapse assembly and hearing restoration in the deafened inner ear. This multi-investigator collaborative project draws on the complementary expertise of Michele Jacob (molecular mechanisms of neuronal synapse assembly), Yehoash Raphael (sensory hair cell regeneration), and Keith Duncan (ion channel function in sensory hair cells). We will focus on efferent olivocochlear (OC) cholinergic inputs from the brain onto sensory hair cells. OC cholinergic activity regulates the sensitivity and frequency selectivity of hearing. ¿9/10-containing nicotinic acetylcholine receptors (nAChRs) mediate synaptic transmission in hair cells. Further, normal activity requires the functional coupling and close positioning of ¿9/10-nAChRs to small conductance calcium activated potassium channels (SK2). Early SK2 expression is also required for inner hair cell functional maturation and normal exocytotic activity at the afferent presynaptic inputs onto primary auditory neurons that signal sound reception to the brain. Mechanisms that direct the synaptic localization of ¿9/10- nAChRs and SK2 channels are undefined. We predict the molecular organization of the OC synapse based on our identification of key components at neuronal ¿3-nAChR synapses and preliminary findings of shared components at hair cell ¿9/10-nAChR synapses. In Aim1, we will define the core postsynaptic complex of scaffold and cytoskeletal regulatory proteins at avian OC synapses. Aim2 will define the specific adapter proteins that link ¿9/10-nAChRs and SK2 channels to postsynaptic complex components. Aim3 will test the in vivo roles of the adapter proteins in directing ¿9/10-nAChR and SK2 synaptic localization and functional coupling that are essential for normal hearing. We will test the model in avian developing and regenerated hair cells. We will use loss-of-function and gain-of-function strategies and exploit the spontaneous regeneration and reverse genetic, molecular, morphological, biochemical and functional advantages of chick sensory hair cells. Our findings will provide new insights into the molecular organization of nicotinic synapses in both developing and regenerated hair cells. We will identify novel binding partners for ¿9/10-nAChRs and SK2 channels. Further, the studies will provide the first identification of molecular interactions, in vivo, that are essential for synapse assembly and hearing recovery in the deafened inner ear.
文摘:

项目成果

期刊论文数量(0)
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会议论文数量(0)
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Michele H. Jacob其他文献

Use of polyadenosine tail mimetics to enhance mRNA expression from genes associated with haploinsufficiency disorders
使用多聚腺苷酸尾巴模拟物来增强与单倍体不足症相关基因的 mRNA 表达
  • DOI:
    10.1016/j.omtn.2025.102453
  • 发表时间:
    2025-03-11
  • 期刊:
  • 影响因子:
    6.100
  • 作者:
    Bahareh Torkzaban;Yining Zhu;Christian Lopez;Jonathan M. Alexander;Jingyao Ma;Yongzhi Sun;Katharine R. Maschhoff;Wenqian Hu;Michele H. Jacob;Dingchang Lin;Hai-Quan Mao;Sophie Martin;Jeff Coller
  • 通讯作者:
    Jeff Coller

Michele H. Jacob的其他文献

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{{ truncateString('Michele H. Jacob', 18)}}的其他基金

Defining the Potential of Gene Therapy to Correct Motor Disabilities of CTNNB1 Syndrome Using in Vivo Mouse and in Vitro Human Cell Models
利用体内小鼠和体外人类细胞模型确定基因疗法纠正 CTNNB1 综合征运动障碍的潜力
  • 批准号:
    10809254
  • 财政年份:
    2023
  • 资助金额:
    $ 42.57万
  • 项目类别:
Investigating molecular mechanisms and treatments for CTNNB1 Syndrome using mouse and human models
使用小鼠和人类模型研究 CTNNB1 综合征的分子机制和治疗方法
  • 批准号:
    10307411
  • 财政年份:
    2021
  • 资助金额:
    $ 42.57万
  • 项目类别:
Molecular causes of cognitive and autistic disabilities
认知障碍和自闭症障碍的分子原因
  • 批准号:
    9026843
  • 财政年份:
    2016
  • 资助金额:
    $ 42.57万
  • 项目类别:
Molecular causes of cognitive and autistic disabilities
认知障碍和自闭症障碍的分子原因
  • 批准号:
    9917856
  • 财政年份:
    2016
  • 资助金额:
    $ 42.57万
  • 项目类别:
Molecular causes of cognitive and autistic disabilities
认知障碍和自闭症障碍的分子原因
  • 批准号:
    9326368
  • 财政年份:
    2016
  • 资助金额:
    $ 42.57万
  • 项目类别:
Synapse Neurobiology Training Program
突触神经生物学培训计划
  • 批准号:
    8704483
  • 财政年份:
    2009
  • 资助金额:
    $ 42.57万
  • 项目类别:
Molecular mechanisms of auditory nAChR synapse assembly
听觉 nAChR 突触组装的分子机制
  • 批准号:
    8317687
  • 财政年份:
    2009
  • 资助金额:
    $ 42.57万
  • 项目类别:
Synapse Neurobiology Training Program
突触神经生物学培训计划
  • 批准号:
    8263419
  • 财政年份:
    2009
  • 资助金额:
    $ 42.57万
  • 项目类别:
Synapse Neurobiology Training Program
突触神经生物学培训计划
  • 批准号:
    8666395
  • 财政年份:
    2009
  • 资助金额:
    $ 42.57万
  • 项目类别:
Synapse Neurobiology Training Program
突触神经生物学培训计划
  • 批准号:
    9343054
  • 财政年份:
    2009
  • 资助金额:
    $ 42.57万
  • 项目类别:

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