Genetics of Age-related Hearing Loss

年龄相关性听力损失的遗传学

• 批准号: 8399008
• 负责人: KENNETH R JOHNSON
• 金额: $ 41.75万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-05 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399008
• 关键词: A/J Mouse; Aging; Auditory; Bundling; Candidate Disease Gene; Cell physiology; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 5; Chromosomes, Human, Pair 6; Citrate (si)-Synthase; Complex; Development; Diagnostic; Disease; Distal; Elderly; Environmental Risk Factor; Evaluation; Exhibits; Free Radicals; Gamma-glutamyl transferase; Genes; Genetic; Genetic Engineering; Genetic Predisposition to Disease; Genetic Variation; Genome; Glutathione; Goals; Grant; Gray unit of radiation dose; Hair; Hair Cells; Hearing problem; Human; Inbred Strain; Inbred Strains Mice; Inbreeding; Inner Hair Cells; Knock-in Mouse; Knockout Mice; Knowledge; Laboratory mice; Labyrinth; Link; Location; Maps; Measures; Missense Mutation; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Morphology; Mus; Mutant Strains Mice; Mutation; NOD/LtJ Mouse; Nature; Noise; Oxidative Stress; Pathology; Pathway interactions; Pharmaceutical Preparations; Population; Positioning Attribute; Predisposition; Presbycusis; Preventive Intervention; Proteins; Quality of life; RNA Splicing; Research; Role; Sensory; Stereocilium; Testing; Therapeutic Intervention; Time; Tissues; Transgenes; Trauma; Variant; actin 2; base; congenic; early onset; fascin; genetic analysis; hearing impairment; human CDH23 protein; insight; mitochondrial dysfunction; non-genetic; null mutation; programs

DESCRIPTION (provided by applicant): Presbycusis or age-related hearing loss (AHL) is the most common sensory deficit in aging human populations and a major factor in reducing the quality of life of the elderly. Genetic studies in humans are difficult because of the late onset of the condition and because non-genetic factors such as noise trauma, disease, and ototoxic drugs confound interpretations. The laboratory mouse provides promising models for human presbycusis because AHL is common in inbred mouse strains and mice are more amenable to detailed genetic and pathological analyses. Mice and humans often share the same genes and inner ear pathologies underlying monogenic hearing disorders, so genetic studies of AHL in mice are likely to add significantly to our understanding of human presbycusis. Aim 1 of this proposal is to complete the analysis of genetically engineered knock-in mice to verify that a splice variant of the cadherin 23 gene (Cdh23) underlies ahl, a variant conferring AHL susceptibility to multiple inbred strains, and to genetically analyze strain-specific influences on its manifestation. Cdh23 encodes a component of the stereocilia tip link, which is essential to hair cell mechanotransduction, but it is unclear how the Cdh23ahl variant influences AHL. We previously showed that a missense mutation of fascin 2 (FSCN2), an actin bundling protein of hair cell stereocilia, underlies ahl8, a locus on distal Chr 11 that contributes to the early onset hearing loss of DBA/2J mice. Aim 2 of this proposal is to further elucidate the role of FSCN2 in auditory function by examining hair bundle morphology and hearing loss progression in Fscn2 knockout mice, and by genetically mapping strain-specific loci that modify the effect of Fscn2ahl8 on hearing loss. The chromosomal location and strain distribution of a citrate synthase (Cs) missense mutation strongly supports it as a candidate for the ahl4-related hearing loss of A/J mice. Aim 3 is to determine the causative nature of this mutation on AHL by a BAC rescue approach, in which a wild-type Cs transgene is integrated into the genome of A/J mice. Another aspect of this aim is to investigate the effects of the A/J ahl4 (Cs) variant and a previously described mt-Tr variant on mitochondrial function and oxidative stress in cochlear tissues. We recently discovered that mice with a null mutation of gamma-glutamyltransferase 1(Ggt1), which are glutathione deficient, exhibit a progressive hearing loss that is associated with a selective loss of cochlear inner hair cells. Aim 4 is to examine in detail the progression of inner ear pathologies and to measure glutathione-related oxidative stress parameters related to the hearing loss of Ggt1 mutant mice. Aim 5 of this proposal is to refine the chromosomal locations and test candidate genes for three newly mapped loci that contribute to AHL in A/J mice (ahl9 on Chr 11) and NOD/ShiLtJ mice (ahl10 on Chr 1 and ahl11 on Chr 6).

描述（由申请人提供）：老年性耳聋或年龄相关性听力损失（阿勒）是老年人群中最常见的感觉缺陷，也是降低老年人生活质量的主要因素。人类的遗传学研究是困难的，因为这种疾病的发病较晚，而且非遗传因素，如噪音创伤，疾病和耳毒性药物混淆了解释。实验室小鼠为人类老年性耳聋提供了有希望的模型，因为阿勒在近交系小鼠中很常见，并且小鼠更适合详细的遗传和病理分析。小鼠和人类通常具有相同的基因和单基因听力障碍的内耳病理，因此小鼠阿勒的遗传研究可能会大大增加我们对人类老年性耳聋的理解。本提案的目的1是完成基因工程敲入小鼠的分析，以验证钙粘蛋白23基因（Cdh 23）的剪接变体是阿勒的基础，该变体赋予阿勒对多个近交系的易感性，并对其表现进行遗传分析。Cdh 23编码静纤毛尖端连接的一个成分，这对于毛细胞机械传导至关重要，但目前尚不清楚Cdh 23 ahl变体如何影响阿勒。我们先前表明，fascin 2（FSCN 2）的错义突变，毛细胞静纤毛的肌动蛋白捆绑蛋白，是ahl 8的基础，ahl 8是远端Chr 11上的一个位点，导致DBA/2 J小鼠的早发性听力损失。该提议的目的2是通过检查Fscn 2敲除小鼠中的毛束形态和听力损失进展，以及通过遗传定位改变Fscn 2ahl 8对听力损失的影响的品系特异性基因座，进一步阐明Fscn 2在听觉功能中的作用。柠檬酸合酶（Cs）错义突变的染色体位置和菌株分布强烈支持其作为A/J小鼠的ahl 4相关听力损失的候选者。目的3是通过BAC拯救方法确定阿勒上这种突变的致病性质，其中野生型Cs转基因整合到A/J小鼠的基因组中。该目的的另一方面是研究A/J ahl 4（Cs）变体和先前描述的mt-Tr变体对耳蜗组织中线粒体功能和氧化应激的影响。我们最近发现，具有γ-谷氨酰转移酶1（Ggt 1）无效突变的小鼠（谷胱甘肽缺乏）表现出与耳蜗内毛细胞选择性丧失相关的进行性听力丧失。目的4是详细检查内耳病理学的进展，并测量与Ggt 1突变小鼠听力损失相关的谷胱甘肽相关氧化应激参数。该建议的目的5是细化染色体定位并测试三个新定位的基因座的候选基因，这些基因座有助于A/J小鼠（Chr 11上的ahl 9）和NOD/ShiLtJ小鼠（Chr 1上的ahl 10和Chr 6上的ahl 11）中的阿勒。