Identification of ARHL Genes and their Molecular and Functional Modifiers

ARHL 基因及其分子和功能修饰物的鉴定

• 批准号: 9151171
• 负责人: BRUCE L TEMPEL
• 金额: $ 38.62万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9151171
• 关键词: Acoustics; Acute; Affect; Age; Age-Months; Aging; Alleles; Anatomy; Auditory; Auditory Brainstem Responses; Auditory system; CBA/CaJ Mouse; Cochlea; Congenic Mice; Doxycycline; Endolymph; Epithelial; Equilibrium; Evaluation; Extravasation; Family; Frequencies; Gene Expression; Genes; Genetic Transcription; Genetic study; Goals; Hair Cells; Hearing; Hearing Tests; Integral Membrane Protein; Laboratories; Light; Liquid substance; Maps; Measures; Methods; Microfilaments; Modeling; Molecular; Mus; Noise; Organ of Corti; Outer Hair Cells; Perilymph; Permeability; Phenotype; Physiological; Physiology; Potassium; Presbycusis; Proteins; Quantitative Trait Loci; Resistance; Role; Stress; Stria Vascularis; Supporting Cell; Tight Junctions; Tissues; Transgenic Mice; Water; Western Blotting; deafness; dosage; early onset; embryonic stem cell; hearing impairment; in vivo Model; light effects; occludin; resistance gene; ribbon synapse; trait; young adult

PROJECT SUMMARY/ABSTRACT The claudin family is composed of transmembrane proteins that are an essential part of the tight junctions forming barriers in epithelial and endothelial tissue. In the cochlea, Claudin 9 (Cldn9) is highly expressed in the tight junctions of the organ of Corti, where separation of high potassium (K+) endolymph from the low K+ perilymph fluid is necessary for protection of the outer hair cells (OHCs), as well as for maintaining the Endocochlear Potential (EP) (Nakano et al 2009, Wangemann and Schacht, 1996). Our lab has focused on identifying genes that are resistant to noise stress (Street, et al. 2014). Among the five quantitative trait loci (QTL) that appeared in the 129S6/SvEvTac (129S6) strain, the strongest QTL contains Cldn9. Surprisingly, when we started to study the noise sensitivity it became apparent that this locus also displayed an age-related hearing loss (AHL) phenotype that was non-progressive hearing loss (NPHL), and a significant mid-frequency ARHL by 12 months. To explore functional attributes of Cldn9, we have recently developed a Doxycyline (dox) regulated version of the Cldn9 gene that can be up or down regulated. We are assured that the changes that we observe after dox manipulation are due to the Cldn9 expression. Here we will examine the role of Cldn9 in an aging auditory system, including the influence noise and the question of Cldn9’s role in potassium leakage.

项目总结/摘要 密蛋白家族由跨膜蛋白组成，这些蛋白是紧密连接的重要组成部分 在上皮和内皮组织中形成屏障。在耳蜗中，Claudin 9（Cldn 9）在耳蜗中高度表达。 Corti器的紧密连接，高钾（K+）内淋巴与低钾（K+）内淋巴的分离 外淋巴液对于保护外毛细胞（OHC）以及维持外毛细胞的生长是必需的。 耳蜗内电位（EP）（中野等人，2009年，Wangemann和Schacht，1996年）。 我们的实验室专注于识别抗噪音压力的基因（Street，et al. 2014）。五个 在129 S6/SvEvTac（129 S6）品系中出现的数量性状基因座（QTL）中，最强的QTL含有 Cldn9.令人惊讶的是，当我们开始研究噪音敏感性时，很明显，这个位点也 表现出与年龄相关的听力损失（阿勒）表型，即非进行性听力损失（NPHL），以及与年龄相关的听力损失（AHL）表型，即非进行性听力损失（NPHL）。 12个月时出现显著的中频ARHL。 为了探索Cldn 9的功能属性，我们最近开发了Doxycyline（dox）调节的Cldn 9变体。 可以上调或下调的Cldn 9基因。我们确信，我们在dox之后观察到的变化 操纵是由于Cldn 9表达。在这里，我们将研究Cldn 9在衰老的听觉系统中的作用。 系统，包括影响噪声和Cldn 9的钾渗漏的作用的问题。