Pathophysiology of hearing loss associated with Connexin 26 dysfunction

与连接蛋白 26 功能障碍相关的听力损失的病理生理学

基本信息

批准号：
9023355
负责人：
Dylan Chan
金额：
$ 15.85万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9023355
关键词：
Accounting Acoustic Trauma Acoustics Address Adult Affect Animals Area Auditory Auditory Brainstem Responses Behavior Cells Characteristics Child Childhood Cochlea Development Ear Functional disorder GJB2 gene Gap Junctions Gene Dosage Genetic Genetic Models Gerbils Hair Cells Hearing Heterozygote Histology Human Impairment Individual Kinetics Knock-out Label Learning Literature MAP Kinase Gene Mediating Modeling Molecular Profiling Mus Mutation Natural regeneration Neonatal Noise Noise-Induced Hearing Loss Organ Pathway interactions Phenotype Phosphorylation Physiological Point Mutation Predisposition Recycling Role Sensory Signal Transduction Structural defect Supporting Cell Synapses Tamoxifen Trauma base hearing impairment human disease in vitro Model knockout gene mature animal mutant programs public health relevance repaired response targeted treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Hearing loss is the most common congenital sensory impairment. Mutations in Connexin 26 (Cx26) comprise the most common genetic causes of hearing loss. Cx26 forms gap junctions in supporting cells of the cochlea, but the pathophysiology of Cx26- associated hearing impairment is unclear. Mouse studies have suggested major roles in cochlear development and mature function: 1) in the neonatal period, gap-junction- mediated intercellular Ca2+ signaling (ICS) waves are necessary for functional maturation, and Cx26 knockout results in major structural abnormalities; 2) in hearing- mature animals, gap junctions may be involved in K+ recycling, cochlear amplification, and an ICS and MAPK-dependent response to acoustic trauma that recapitulates their developmental role. The hearing-loss phenotype of Cx26 dysfunction in humans is highly variable and mutation-dependent, suggesting that differential effects on the developmental and functional roles of Cx26 may be meaningful. In order to develop targeted therapy for different kinds of Cx26-associated hearing loss, a thorough understanding of its pathophysiologic mechanisms is required. In this study, we address a major limitation in the literature surrounding the pathophysiology of Cx26-associated hearing loss. The vast majority of studies have been conducted in neonatal mice with early, complete cochlea-specific knockout of Cx26 and subsequent cochlear developmental abnormalities. We aim to 1) evaluate the role of ICS and gap junctions in an ex vivo model of the hearing gerbil cochlea; and 2) investigate the consequences of functional derangements in Cx26 (through an inducible conditional knockout, gene dosage model, and specific functional point mutations) in the otherwise normally developed mouse cochlea. Phenotype will be assessed both at the organ level, by assessing gap-junction function, ICS behavior, and expression profiles of gap-junction constituents, downstream MAPK effectors, and synaptic labeling, and at the whole-animal physiologic level, by evaluating auditory brainstem responses and noise- induced hearing loss. By determining how Cx26 dysfunction affects cochlear and auditory function, we will be able to develop targeted therapies for a wide range of individuals with Cx26-associated hearing loss.

描述（由申请人提供）：听力损失是最常见的先天性感觉障碍。连接蛋白 26 (Cx26) 突变是听力损失最常见的遗传原因，但 Cx26 的病理生理学是在耳蜗支持细胞中形成间隙连接。 - 相关的听力障碍尚不清楚。小鼠研究表明其在耳蜗发育和成熟功能中的主要作用：1）在新生儿期，间隙连接介导的细胞间 Ca2+ 信号传导 (ICS) 波对于功能成熟是必需的，Cx26 敲除会导致主要的结构异常；2) 在听力成熟的动物中，间隙连接可能参与 K+ 循环、耳蜗放大和 ICS。人类 Cx26 功能障碍的听力损失表型具有高度可变性和突变依赖性，这表明对发育和功能的影响不同。 Cx26 的作用可能是有意义的，为了开发针对不同类型的 Cx26 相关听力损失的靶向治疗，需要彻底了解其病理生理机制。在这项研究中，我们解决了有关 Cx26 病理生理学的文献中的一个主要局限性。绝大多数研究是在早期、完全耳蜗特异性敲除 Cx26 和随后的耳蜗发育异常的新生小鼠中进行的。听力沙鼠耳蜗离体模型中的 ICS 和间隙连接；2) 研究 Cx26 功能紊乱（通过诱导条件敲除、剂量基因模型和特定功能点突变）在其他正常发育的小鼠耳蜗中的后果表型将在器官水平上进行评估，通过评估间隙连接功能、ICS 行为和间隙连接成分的表达谱、下游 MAPK 效应器和突触标记，以及在整个动物生理水平上，通过评估听觉脑干反应和噪音引起的听力损失，通过确定 Cx26 功能障碍如何影响耳蜗和听觉功能，我们将能够为广泛的 Cx26 相关听力个体开发靶向治疗。损失。