Patterning the tonotopic axis of the cochlea

耳蜗的音调轴模式

• 批准号: 8308743
• 负责人: Benjamin R Thiede
• 金额: $ 2.94万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308743
• 关键词: Acoustic Trauma; Affect; Agonist; Apical; Auditory; Birds; Brain; Cell Death; Cells; Cellular biology; Cochlea; Data; Development; Discrimination; Distal; Ensure; Environment; Exhibits; F-Actin; Frequencies; Future; Gene Expression Profile; Generations; Genes; Goals; Hair Cells; Hearing; Height; Human; In Vitro; Ion Channel; Labyrinth; Length; Literature; Location; Mammals; Mesenchyme; Natural regeneration; Nature; Nervous system structure; Pattern; Phenotype; Process; Receptor Cell; Research; Role; Sensory; Sensory Receptors; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Source; Speech; Stereocilium; Structure; Testing; Vertebrates; deafness; extracellular; hair cell regeneration; hearing impairment; hindbrain; in vivo; morphogens; next generation; response; restoration; sound; sound frequency

DESCRIPTION (provided by applicant): Humans and other vertebrates sense sounds over a wide range of frequencies, and being able to hear across this range is critical for properly perceiving the surrounding environment as well as understanding speech. Sound perception originates in the cochlea, which is topologically tuned along its longitudinal axis, with the dista (apical) end tuned to low frequency sounds and the proximal (basal) end tuned to high frequencies. Patterning of the cochlea along this axis of sensitivity is required for proper auditoy function, and the broad, long-term goal of this proposal is to gain an understanding of how this patterning occurs during development. The cochlea contains specialized sensory receptor cells called hair cells (HC), which convert sound into electrical signals, which are then transduced to higher processing centers in the brain. Humans and other mammals incur permanent hearing loss when these auditory HCs are lost. Therapies that replace lost sensory cells must ensure that the new hair cells establish the anatomical patterning essential for generating the tonotopic gradient needed for frequency discrimination. HCs contain apically protruding F-actin rich structures called stereocilia, which form tightly packed arrays of rows of increasing height. There exist structural gradients of stereocilia height and number in the HCs across the tonotopic axis of the chick cochlea. HCs contain ~50 stereocilia that reach a maximum height of 5.5 ?m in the extreme apical (distal) end and ~250 stereocilia that reach 1.5 ?m at the basal (proximal) end (Tilney and Saunders, 1983). These structural differences also have functional importance in the tuning of HCs to different sound frequencies - shorter bundles respond to high frequency sounds and taller bundles respond to low frequency sounds (Frishkopf and DeRosier, 1983; Holton and Hudspeth, 1983). Furthermore, this spatial gradient has also been observed in mammals (Lim, 1980, 1986). This gradient of hundreds of cell phenotypes serves as an excellent readout of the patterning of the cochlea along the tonotopic axis due to its unique quantifiable nature. I have established three aims to gain an understanding of the tonotopic patterning mechanism. I aim to discover whether diffusible signals required for patterning the tonotopic axis of the cochlea are located intrinsically within the avian cochlea. I also aim to sequence the transcriptome across the longitudinal axis of the cochlea to discover differentially expressed genes and signaling pathways that may underlie this patterning. Finally, I aim to modulate candidate signaling pathways in vitro and in ovo to determine whether such manipulations disrupt normal patterning of HC phenotypes along the longitudinal axis of the cochlea. PUBLIC HEALTH RELEVANCE: Proper development and patterning of the hair cells along the length of the cochlea is required for normal auditory function. Damage or loss of these hair cells causes permanent deafness, and therapies that replace lost sensory cells must ensure that the new hair cells establish the anatomical patterning essential for generating the tonotopic gradient needed for functional auditory restoration.

描述（由申请人提供）：人类和其他脊椎动物在广泛的频率上感知声音，并且能够在此范围内听到的声音对于正确感知周围环境以及理解语音至关重要。声音感知起源于耳蜗，该耳蜗沿其纵向轴进行拓扑调节，端（顶）末端调整为低频声音，近端（基底）末端调谐到高频。适当的审计功能需要对耳蜗的构图，而该提案的广泛，长期目标是了解这种图案在开发过程中的发生方式。 耳蜗包含称为毛细胞（HC）的专业感觉受体细胞，它们将声音转换为电信号，然后将其转换为大脑中较高的加工中心。当这些听觉HC丢失时，人类和其他哺乳动物会导致永久性听力损失。替代丢失的感觉细胞的疗法必须确保新的毛细胞为产生频率歧视所需的调整梯度所必需的解剖图案。 HC含有顶尖的F-肌动蛋白富含立体胶质的结构，该结构形成高度增加的行的紧密堆积阵列。那里 存在于HCS的立体胶质高度和数量的结构梯度，跨小鸡耳蜗的吨位轴。 HC含有约50个立体胶质，在极端顶端（远端）的最大高度达到5.5？m，在基础（近端）末端达到1.5 m的立体胶质（Tilney and Saunders，1983）。这些结构性差异在将HC调整为不同声音频率的调整中也具有功能重要性 - 较短的束对高频声音响应，较高的束对低频声音有反应（Frishkopf和Derosier，1983; Holton and Hudspeth，1983）。此外，在哺乳动物中也观察到了这种空间梯度（Lim，1980，1986）。由于其独特的可量化性质，这种数百种细胞表型的梯度是对耳蜗的模式的出色读数。 我已经建立了三个目标，以了解整形图案机制。我的目的是发现对耳蜗的构造轴心轴的图案是否本质地位于鸟类耳蜗内。我还旨在对耳蜗的纵向轴进行转录组，以发现差异表达的基因和信号传导途径，这些基因可能是这种模式的基础。最后，我的目标是在体外和OVO中调节候选信号通路，以确定这种操作是否破坏了沿耳蜗纵轴的HC表型的正常模式。 公共卫生相关性：正常听觉功能需要沿耳蜗长度的毛细胞的正确发育和模式。这些毛细胞的损伤或损失会导致永久性耳聋，替代损失的感觉细胞的疗法必须确保新的毛细胞为产生功能性听觉恢复所需的吨位梯度所必需的解剖图案建立了必不可少的解剖图案。