Functional development of hair cells and neurons in the inner ear

内耳毛细胞和神经元的功能发育

• 批准号: 10528453
• 负责人: Gwenaelle S Geleoc
• 金额: $ 57.18万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10528453
• 关键词: Action Potentials; Address; Affect; Afferent Neurons; Auditory; Auditory system; Birth; Brain; Calcium; Cell Maturation; Cell Survival; Cell physiology; Cells; Closure by clamp; Cochlea; Development; Discrimination; Electrodes; Electrophysiology (science); Embryo; Event; Exhibits; Exocytosis; Fiber; Fire - disasters; Functional disorder; Genes; Glutamates; Hair; Hair Cells; Hearing; Human; Image; Impairment; Inner Hair Cells; Labyrinth; Life; Maintenance; Mechanics; Mediating; Modeling; Morphology; Mus; Mutant Strains Mice; Neonatal; Neurons; Organ; Organ of Corti; Outcome; Outer Hair Cells; Patients; Pattern; Potassium; Process; Property; RNA; Recovery; Sampling; Sensory; Signal Transduction; Specific qualifier value; Synapses; Synaptic Transmission; Technology; Thinness; Tinnitus; Transcript; Transduction Gene; Vesicle; Vestibular Hair Cells; Wild Type Mouse; Work; cellular transduction; deafness; gene therapy; hearing restoration; hereditary hearing loss; high resolution imaging; inner ear development; mouse model; neuronal patterning; neurotransmission; novel therapeutics; postnatal; postsynaptic; presynaptic; receptor; restoration; ribbon synapse; single-cell RNA sequencing; sound; speech in noise; spiral ganglion; superresolution microscopy; synaptogenesis; transmission process; voltage

Project summary Hair cells of the inner ear are the primary receptors of the auditory system. They transduce mechanical information, associated with sound waves, into electro-mechanical (outer hair cells) and electro-chemical (Inner hair cells) signals, which lead to amplification of the initial signal and activation of afferent neuronal fibers, respectively. While hair cells and neuronal fibers appear before birth in mice, development and maturation of the hair cells, neurons and synapses proceeds until hearing onset, ~postnatal day 12. This process is believed to be dynamic and modulated by hair cell activity. In particular, recent work has shown that lack of hair cell transmission, due to absence of functional synapses or defective mechanosensation, leads to altered neuronal maturation and specification. Successful outcomes for new therapies, including gene therapy, aimed at restoring hair cell function after birth, may depend on restoration of auditory circuits, including mature and functional hair cell synapses and neuronal fibers. Here we propose to assess how disruption or loss of sensory transduction in several mouse models affects hair cell function, synaptic maturation and spiral ganglion specification. Furthermore, we will determine if inner ear gene therapy is capable of reversing any of these observed changes and identify the conditions for optimal recovery of auditory function. We will combine state-of-the-art technologies to address these important questions, including high-resolution imaging, electrophysiology, single cell RNA sequencing and localization of RNA transcripts.

项目摘要 内耳的毛细胞是听觉系统的主要感受器。它们是机械的 信息，与声波，进入机电（外毛细胞）和电化学（内 毛细胞）信号，其导致初始信号的放大和传入神经元纤维的激活， 分别虽然小鼠的毛细胞和神经元纤维在出生前就出现了，但毛细胞的发育和成熟， 毛细胞、神经元和突触的发育一直持续到出生后第12天开始出现听力。这一过程被认为是 是动态的并由毛细胞活动调节。特别是，最近的研究表明，缺乏毛细胞， 由于功能性突触的缺乏或机械感觉缺陷，传递导致神经元的改变， 成熟和规范。新疗法的成功结果，包括基因疗法，旨在恢复 毛细胞功能出生后，可能取决于恢复听觉回路，包括成熟和功能 毛细胞突触和神经纤维。在这里，我们建议评估如何中断或损失的感觉转导 在几种小鼠模型中影响毛细胞功能、突触成熟和螺旋神经节特化。 此外，我们将确定内耳基因治疗是否能够逆转任何这些观察到的变化 并确定听觉功能最佳恢复的条件。我们将联合收割机 解决这些重要问题的技术，包括高分辨率成像，电生理学，单 细胞RNA测序和RNA转录物的定位。