Molecular biology of cochlear efferent receptors

耳蜗传出受体的分子生物学

基本信息

批准号：
7844229
负责人：
ANNE E LUEBKE
金额：
$ 4.97万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844229
关键词：
Acoustics Action Potentials Adult Afferent Neurons Animals Auditory Auditory Brainstem Responses Auditory system Biochemical Biolistics Brain Stem CALCA gene Calcitonin Gene-Related Peptide Calcitonin-Gene Related Peptide Receptor Cavia Cells Cochlea Cochlear Nerve Complex Control Animal Cyclic AMP Data Dendrites Development Dominant-Negative Mutation Ear Epithelium Event Exhibits Feedback Fiber Fluorescence Resonance Energy Transfer G-Protein-Coupled Receptors Gene Transfer Goals Hair Cells Hearing Image Immunohistochemistry In Situ Indium Inner Hair Cells Ipsilateral Knock-out Knockout Mice Lateral Measures Medial Mediating Methods Molecular Molecular Biology Mus Nerve Neurons Neurotransmitters Nicotinic Receptors Noise Organ Outer Hair Cells Pathway interactions Phenotype Physiological Predisposition Process RAMP1 Receptor Signaling Sensory Signal Transduction System Testing Time Tissues Transfection Work Xenopus base calcitonin receptor-like receptor ganglion cell in vivo lateral line nerve supply otoacoustic emission receptor relating to nervous system research study sound spiral ganglion

项目摘要

DESCRIPTION (provided by applicant): All hair cell systems, including lateral-line organs, vestibular organs and the cochlea, contain an efferent innervations, originating in the brainstem and projecting to the hair cells and/or neural elements in the sensory epithelium. In the mammalian cochlea, this efferent system originates in the superior olivary complex and has been called the olivocochlear (OC) pathway and consists of a medial (MOC) and lateral (LOC) component. Cochlear efferent is likely to serve two functions: protection from acoustic over stimulation and enhancement of sound recognition in the presence of background noises. In the last project period, we determined that the MOC efferent could protect the cochlea from acoustic over stimulation working through the newly discovered alpha 9/10 nACh receptor complex. In this next project period, we will focus on the LOC efferent fibers that contain calcitonin gene-related peptide (CGRP). We determined that the loss of CGRP in knockout mice reduced sound-evoked activity of the cochlear nerve, which would then cause a reduction in the dynamic range of sound perception. However there are several CGRP-ergic neuronal systems in hair cell organs: the efferent as well as pathways innervating the vasculature, which could have contributed to the auditory phenotype. Our goal is to determine the molecular mechanism by which CGRP released from efferent fibers influences neuronal afferents. In these aims we will (1) determine effect of CGRP receptor signaling on sound-evoked activity; (2) determine biochemical time course for CGRP receptor signaling; (3) determine physiological target cells for CGRP receptor signaling. We will use adenoviral gene transfer, DPOAE, ABR, and CAP testing for auditory function, immunohistochemisty, coimmunoprecipitation, biolistic transfection, and FRET imaging to carry out these aims. Information gained from these studies will provide direct assessment of the molecular mechanisms used by the CGRP efferent feedback pathway to enhance sound-evoked activity in the cochlear nerve.

描述（由申请人提供）：所有毛细胞系统，包括侧线器官、前庭器官和耳蜗，都包含传出神经支配，起源于脑干并投射到感觉上皮中的毛细胞和/或神经元件。在哺乳动物耳蜗中，该传出系统起源于上橄榄复合体，被称为橄榄耳蜗 (OC) 通路，由内侧 (MOC) 和外侧 (LOC) 部分组成。耳蜗传出神经可能具有两种功能：防止声音过度刺激以及在背景噪音存在的情况下增强声音识别能力。在上一个项目期间，我们确定 MOC 传出神经可以通过新发现的 α 9/10 nACh 受体复合物保护耳蜗免受声学过度刺激。在下一个项目期间，我们将重点关注含有降钙素基因相关肽 (CGRP) 的 LOC 传出纤维。我们确定，基因敲除小鼠中 CGRP 的缺失会降低耳蜗神经的声音诱发活动，从而导致声音感知的动态范围缩小。然而，毛细胞器官中有几种 CGRP 能神经元系统：传出神经系统以及支配脉管系统的通路，这可能有助于听觉表型。我们的目标是确定传出纤维释放的 CGRP 影响神经元传入的分子机制。为了实现这些目标，我们将 (1) 确定 CGRP 受体信号传导对声音诱发活动的影响； (2)确定CGRP受体信号转导的生化时程； (3)确定CGRP受体信号转导的生理靶细胞。我们将使用腺病毒基因转移、DPOAE、ABR 和 CAP 听觉功能测试、免疫组织化学、免疫共沉淀、基因枪转染和 FRET 成像来实现这些目标。从这些研究中获得的信息将直接评估 CGRP 传出反馈通路用于增强耳蜗神经声音诱发活动的分子机制。