Mechanisms of Growth Factor Responsiveness in the Aging Auditory System

衰老听觉系统中生长因子反应的机制

基本信息

  • 批准号:
    9896749
  • 负责人:
  • 金额:
    $ 54.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-08-15 至 2023-03-31
  • 项目状态:
    已结题

项目摘要

Abstract: During hearing development, auditory neurons are wired correctly, both qualitatively and quantitatively, with specific types of spiral ganglion neurons (SGN; auditory afferents) and cochlear nucleus (CN) nerve fibers. Maturation of the auditory neural pathway ensues along the functional tonotopic frequency axis, apparently correlating with time and space/location-dependent gradients in neurotrophins (NTs). In addition, the SGNs develop cochleotopic responses to sound and achieve cochleotopic projections to the cochlear nuclei (CN). The activity of SGNs maintains the number, size and functions of cells in the CN. Previous studies suggest that this process is regulated in part by neurotrophic factors (e.g. brain-derived neurotrophic factor (BDNF)). Expression data show that BDNF expression undergo developmental and age-dependent shifts in their cellular and longitudinal patterns of expression in the auditory pathway. This pattern was proposed to dictate distinct apico- basal function of auditory neuron electrical properties, in turn requirements for cochleotopic and central auditory neuron fine tuning. Despite the appeal of the NT-gradient and age-dependent hypothesis for auditory neural properties, this idea rests on correlative evidence, disputed by some. We seek to unequivocally test and clarify the NT-gradient predictions, and to understand BDNF-mediated auditory functional plasticity and how it sculpts age-related hearing loss (ARHL). We hypothesize that gradual decline in BDNF signaling is one of the common cause for ARHL. We will unravel the function of BDNF in auditory neuronal plasticity using well-characterized cre lines (e.g. Rosa26-creER; Fgf8-cre, Atoh1-cre) to selectively reduce or eliminate BDNF in floxed lines, to study the long- term influence of BDNF levels on auditory signal processing in aging mice. In Aim 1, we will quantify BDNF signaling expression in the auditory system, determine the source/s and the ensuing age-related changes in the auditory neural pathway. Single molecule fluorescent in situ hybridization (SmFISH) and immunocytochemical techniques will be used to quantify mRNA and protein expression and the age-related changes of BDNF. Additionally, age-related changes in BDNF-receptors expression will be quantified. In Aim 2, we will determine BDNF-mediated auditory plasticity with partial or delayed loss of BDNF. These goals will be accomplished using inducible cre lines (e.g. Rosa26-creER) to eliminate all BDNF at various stages of aging from ~3-week to 2-year old mice. We will determine the age-related cellular properties of auditory neurons (e.g. SGNs). Finally, in Aim 3, we will identify BDNF-mediated neural and synaptic plasticity with partial and delayed loss of BDNF. We will use the animal models outlined in Aim 2 to identify changes in synaptic function at the calyx of Held, due to BDNF loss/decline. This central auditory synapse, originates in the ventral cochlear nucleus (VCN), and project contralaterally to the medial nucleus of the trapezoid body (MNTB), and is found to undergo morphological and molecular alterations during aging. We will also examine CN functional changes. Thus, we will resolve how the expression of BDNF impacts SGN/VCN/MNTB functions during aging, providing evidence for BDNF signaling as a common cause for auditory decline. This knowledge will inform efforts to use BDNF in therapeutic strategies to preserve auditory neuron viability and function after ARHL.
文摘:

项目成果

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BERND FRITZSCH其他文献

BERND FRITZSCH的其他文献

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{{ truncateString('BERND FRITZSCH', 18)}}的其他基金

Mechanisms of Growth Factor Responsiveness in the Aging Auditory System
衰老听觉系统中生长因子反应的机制
  • 批准号:
    10202470
  • 财政年份:
    2018
  • 资助金额:
    $ 54.37万
  • 项目类别:
Mechanisms of Growth Factor Responsiveness in the Aging Auditory System
衰老听觉系统中生长因子反应的机制
  • 批准号:
    9762822
  • 财政年份:
    2018
  • 资助金额:
    $ 54.37万
  • 项目类别:
Mechanisms of Growth Factor Responsiveness in the Aging Auditory System
衰老听觉系统中生长因子反应的机制
  • 批准号:
    10377515
  • 财政年份:
    2018
  • 资助金额:
    $ 54.37万
  • 项目类别:
DISSECTING THE EAR NEUROSENSORY DEVELOPMENT.
剖析耳朵神经感觉发育。
  • 批准号:
    7809961
  • 财政年份:
    2009
  • 资助金额:
    $ 54.37万
  • 项目类别:
EMBRYONIC DEVELOPMENT OF THE EFFERENT SYSTEM
传出系统的胚胎发育
  • 批准号:
    6564033
  • 财政年份:
    2002
  • 资助金额:
    $ 54.37万
  • 项目类别:
DISSECTING THE EAR NEUROSENSORY DEVELOPMENT.
剖析耳朵神经感觉发育。
  • 批准号:
    7145833
  • 财政年份:
    2002
  • 资助金额:
    $ 54.37万
  • 项目类别:
DISSECTING THE EAR NEUROSENSORY DEVELOPMENT.
剖析耳朵神经感觉发育。
  • 批准号:
    7620368
  • 财政年份:
    2002
  • 资助金额:
    $ 54.37万
  • 项目类别:
DISSECTING THE EAR NEUROSENSORY DEVELOPMENT.
剖析耳朵神经感觉发育。
  • 批准号:
    7826769
  • 财政年份:
    2002
  • 资助金额:
    $ 54.37万
  • 项目类别:
Cellular Interactions During Ear Development
耳朵发育过程中的细胞相互作用
  • 批准号:
    6794827
  • 财政年份:
    2002
  • 资助金额:
    $ 54.37万
  • 项目类别:
Cellular Interactions During Ear Development
耳朵发育过程中的细胞相互作用
  • 批准号:
    6646478
  • 财政年份:
    2002
  • 资助金额:
    $ 54.37万
  • 项目类别:

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