Genetics of Age-related Hearing Loss

年龄相关性听力损失的遗传学

• 批准号: 8234487
• 负责人: KENNETH R JOHNSON
• 金额: $ 45.94万
• 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/8234487
• 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; Engineering; Environmental Risk Factor; Evaluation; Exhibits; Free Radicals; Gamma-glutamyl transferase; Genes; Genetic; 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). PUBLIC HEALTH RELEVANCE: 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. AHL is common in inbred mouse strains, and mice are more amenable to detailed genetic and pathological analyses, which could add significantly to our understanding of presbycusis in humans.

描述(申请人提供)：老年性耳聋或年龄相关性听力损失(AHL)是老龄化人口中最常见的感觉障碍，也是降低老年人生活质量的主要因素。在人类中进行遗传学研究是困难的，因为这种疾病的发病时间较晚，而且噪音、创伤、疾病和耳毒性药物等非遗传因素会混淆解释。实验室小鼠为人类老年性耳聋提供了有希望的模型，因为AHL在近亲交配的小鼠品系中很常见，而且小鼠更容易接受详细的遗传和病理分析。小鼠和人类经常共享相同的基因和单基因听力障碍背后的内耳病理，因此对小鼠AHL的遗传学研究可能会大大增加我们对人类老年性耳聋的理解。该方案的目的1是完成对基因工程敲入小鼠的分析，以证实钙粘蛋白23基因的剪接变体(CDH23)是AHL的基础，该变体使AHL对多种近交系易感，并从遗传学角度分析不同品系对其表现的影响。CDH23编码毛细胞机械转导所必需的立体纤毛顶端连接的一个组成部分，但尚不清楚CDH23ah1变体如何影响AHL。我们先前的研究表明，毛细胞立体纤毛的肌动蛋白束蛋白FSCN 2(FSCN 2)的错义突变位于H18基因之下，该基因位于DBA/2J小鼠的Chr11末端，与早发性听力损失有关。该建议的目的2是通过研究Fscn2基因敲除小鼠的毛束形态和听力损失进展，以及通过基因定位改变Fscn2ahl8对听力损失的影响的品系特异性基因座，进一步阐明Fscn2在听觉功能中的作用。柠檬酸合成酶(Cs)错义突变的染色体位置和品系分布强烈支持它作为A/J小鼠ah14相关听力损失的候选基因。目的3是通过BAC救援法，将野生型Cs转基因整合到A/J小鼠的基因组中，以确定该突变在AHL上的致病性质。本研究的另一个目的是研究A/J ahl4(Cs)变异体和先前描述的mt-Tr变异体对耳蜗组织线粒体功能和氧化应激的影响。我们最近发现，谷氨酰转移酶1(GGT1)零突变的小鼠是谷胱甘肽缺乏的，表现出进行性听力损失，这与选择性耳蜗内毛细胞的丧失有关。目的4是详细研究Ggt1突变小鼠内耳病变的进展，并测量与Ggt1突变小鼠听力损失相关的谷胱甘肽相关氧化应激参数。这项建议的目的5是改进染色体位置并测试A/J小鼠(在Chr 11上有ah19)和NOD/ShiLtd J小鼠(在Chr 1上有ahl10和在Chr 6上有ah11)三个新定位的AHL候选基因。 公共卫生相关性：老年性耳聋或年龄相关性听力损失(AHL)是老龄化人口中最常见的感觉障碍，也是降低老年人生活质量的主要因素。在人类中进行遗传学研究是困难的，因为这种疾病的发病时间较晚，而且噪音、创伤、疾病和耳毒性药物等非遗传因素会混淆解释。AHL在近交系小鼠中很常见，小鼠更容易接受详细的遗传和病理分析，这可能会大大增加我们对人类老年性耳聋的理解。