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Contribution of COMT2 to auditory processing in mammalian sensory hair cells

COMT2 对哺乳动物感觉毛细胞听觉处理的贡献

基本信息

批准号：
9332057
负责人：
Christopher L Cunningham
金额：
$ 3.87万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332057
关键词：
Acute Affect Afferent Neurons Antibodies Auditory Auditory Perception Auditory system Binding Brain Stem CRISPR/Cas technology Catechol O-Methyltransferase Catecholamines Cell Death Cell physiology Cells Chimeric Proteins Cochlea Communication Data Defect Development Disease Efferent Neurons Electron Microscopy Electrophysiology (science)Ethylnitrosourea Etiology Event Gene Mutation Generations Genes Genetic Genetic study Goals Hair Hair Cells Hearing Hearing Impaired Persons Homologous Gene Human Immunohistochemistry In Situ Hybridization In Vitro Inherited Inner Hair Cells Knock-out Knockout Mice Laboratories Labyrinth Lead Letters Link LoxP-flanked allele Mechanics Messenger RNA Methyltransferase Minor Missense Mutation Molecular Mus Mutagenesis Mutant Strains Mice Mutation Nature Nervous system structure Neurons Outer Hair Cells Pattern Peripheral Physiological Physiological Processes Point Mutation Process Property Proteins Publishing Quality of life Research Role Sense Organs Sensory Sensory Hair Signal Transduction Site Speed Stimulus Synapses Techniques Technology Testing Time Work abstracting base cell type critical period deafness hearing impairment insight metabolomics mutant neurotransmission neurotransmitter release null mutation research study ribbon synapse signal processing sound spiral ganglion synaptic function

项目摘要

Project Summary/Abstract Hearing loss is the most prevalent sensory deficit in humans and causes a significant toll on the quality of life of those afflicted. The mammalian cochlea initiates the perception of sound by converting sound waves into electrical signals with exquisite sensitivity, speed and precision. Mechanotransduction in sensory hair cells leads to electrochemical signals that induce neurotransmitter release from specialized ribbon synapses, initiating the neural signal for auditory processing. The molecular composition of the auditory processing machinery in hair cells is not well understood, and the nature of how specific molecular interactions lead to physiological events for the processing of sound is unclear. Over 100 nonsyndromic forms of genetic hearing loss have been described but many of the genes linked with these mutations are unknown or not well characterized. Mutations in Catechol-O- methyltransferase 2 (COMT2) cause nonsyndromic recessive deafness (DFNB63) in humans. Our lab generated by ENU-mutagenesis a mouse mutant (termed `Add') in which a point mutation in Comt2, the mouse homolog of the human gene, leads to profound deafness. Comt2 mRNA is expressed by hair cells in the inner ear but the manner in which COMT2 contributes to auditory processing in mice and humans is completely unknown. The objective of this proposal is to investigate the role of COMT2 in the peripheral auditory system and the contribution of COMT2 to auditory processing. The hypothesis is that COMT2 contributes to hair cell function and auditory processing by regulating synapse function in the cochlea. Aim 1 will utilize in situ hybridization, immunohistochemistry and immunogold electron microscopy to precisely characterize the cell-specific and temporal expression patterns of Comt2 mRNA in the mouse inner ear and auditory brainstem and the subcellular localization of COMT2 protein in sensory hair cells. Aim 2 will use CRISPR/Cas9 technologies to generate and validate constitutive Comt2 null mice and floxed Comt2 mice to facilitate studies that will examine loss of Comt2 function on peripheral auditory function and auditory processing. Aim 3 will analyze Comt2 mutants to determine the mechanism by which Comt2 contributes to auditory processing in sensory hair cells. By interrogating Comt2 expression patterns and functions within the auditory system, this work will contribute to a better understanding of mechanisms of auditory processing, physiological roles of COMT2, and etiologies of DFNB63 in humans.

项目总结/文摘