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

基本信息

批准号：
10291817
负责人：
Gwenaelle S Geleoc
金额：
$ 54.35万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
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/10291817
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 Lead Life Maintenance Mechanics Mediating Microscopy Modeling Morphology Mus Mutant Strains Mice Neonatal Neurons Organ Organ of Corti Outcome Outer Hair Cells Patients Pattern Potassium Process Property RNA Recovery Resolution Sampling Sensory Signal Transduction Synapses Synaptic Transmission Technology The Sun Thinness Tinnitus Transcript Transduction Gene Vesicle Vestibular Hair Cells Work cellular transduction deafness delta opioid receptor gene therapy hearing restoration hereditary hearing loss high resolution imaging inner ear development mouse development mouse model neuronal patterning neurotransmission novel therapeutics postnatal receptor restoration ribbon synapse single-cell RNA sequencing sound speech in noise spiral ganglion synaptogenesis transmission process voltage

项目摘要

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.

项目概要内耳的毛细胞是听觉系统的主要感受器。他们转换机械与声波相关的信息转化为机电（外毛细胞）和电化学（内毛细胞）毛细胞）信号，导致初始信号放大并激活传入神经元纤维，分别。虽然小鼠的毛细胞和神经元纤维在出生前出现，但毛细胞和神经元纤维的发育和成熟毛细胞、神经元和突触一直持续到出现听力，即出生后第 12 天。这一过程被认为是是动态的并受毛细胞活动调节。特别是，最近的工作表明，缺乏毛细胞由于缺乏功能性突触或机械感觉缺陷，传输会导致神经元改变成熟和规范。新疗法（包括基因疗法）的成功成果旨在恢复出生后的毛细胞功能，可能取决于听觉回路的恢复，包括成熟和功能性的毛细胞突触和神经元纤维。在这里，我们建议评估感觉转导的破坏或丧失如何在一些小鼠模型中，它会影响毛细胞功能、突触成熟和螺旋神经节规格。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。我们将结合最先进的技术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 转录本的定位。