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

• 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
• 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

 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（Cx 26）的突变是导致听力损失的最常见遗传原因。Cx 26在耳蜗的支持细胞中形成缝隙连接，但Cx 26相关的听力障碍的病理生理学尚不清楚。小鼠耳蜗发育和成熟过程中的主要作用是：1）新生期，间隙连接介导的细胞间Ca ~（2+）信号（ICS）波是耳蜗功能成熟所必需的，Cx 26基因敲除导致耳蜗结构异常; 2）在听力成熟的动物中，缝隙连接可能参与K+再循环，耳蜗放大，以及对声损伤的ICS和MAPK依赖性反应，其概括了它们的发育作用。人类Cx 26功能障碍的听力损失表型是高度可变和突变依赖性的，这表明Cx 26的发育和功能作用的差异效应可能是有意义的。为了开发针对不同类型的Cx 26相关性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，我们解决了一个主要的局限性，在文献周围的病理生理学Cx 26相关的听力损失。绝大多数研究都是在新生小鼠中进行的，这些小鼠具有Cx 26的早期、完全耳蜗特异性敲除以及随后的耳蜗发育异常。我们的目的是1）评估ICS和缝隙连接在离体模型的听力沙鼠耳蜗的作用;和2）调查的后果，在Cx 26功能紊乱（通过诱导条件敲除，基因剂量模型，和特定的功能点突变），否则正常发育的小鼠耳蜗。将在器官水平（通过评估间隙连接功能、ICS行为和间隙连接成分、下游MAPK效应物和突触标记的表达谱）和全动物生理水平（通过评价听觉脑干反应和噪声诱导的听力损失）评估表型。通过确定Cx 26功能障碍如何影响耳蜗和听觉功能，我们将能够为广泛的Cx 26相关听力损失个体开发靶向治疗。