Genetics of Age-Related Hearing Loss

年龄相关性听力损失的遗传学

• 批准号: 7534318
• 负责人: KENNETH R JOHNSON
• 金额: $ 31.32万
• 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 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534318
• 关键词: Aging; Backcrossings; Candidate Disease Gene; Chromosome Mapping; Chromosomes, Human, Pair 10; Complex; Development; Diagnostic; Disease; Distal; Elderly; Environmental Risk Factor; Evaluation; Exhibits; Functional disorder; Gene Targeting; Genes; Genetic; Genetic Predisposition to Disease; Goals; Grant; Human; Inbred Strain; Inbred Strains Mice; Knock-in Mouse; Laboratory mice; Labyrinth; Maps; Mitochondria; Modeling; Molecular; Mouse Strains; Mus; Mutation; Nature; Nerve Fibers; Noise; Organ of Corti; Pathology; Pathway interactions; Pharmaceutical Preparations; Population; Positioning Attribute; Predisposition; Presbycusis; Preventive Intervention; Public Health; Quality of life; Research; Sensory; Severities; Stria Vascularis; Study models; Testing; Therapeutic Intervention; Time; Trauma; Variant; Vestibular Hair Cells; base; congenic; ganglion cell; genetic analysis; hearing impairment; improved; insight; non-genetic; research study; spiral ganglion

Project Summary. The genetic basis of age-related hearing loss (presbycusis) is poorly understood because of the extreme difficulty in studying such a late-onset genetically complex disorder. The laboratory mouse provides promising models for studying human presbycusis because age-related hearing loss (AHL) is common in inbred mouse strains and mice are more amenable to genetic analyses. We have shown that a gene on Chromosome 10 (ahl) is a major susceptibility factor for AHL in more than 10 inbred strains of mice and that three other genes (ah!2, ah!4, and a/7/8) and a mitochondrial mutation also contribute to hearing loss in particular inbred strains. We hypothesize that the genetic predisposition and the pathophysiological pathways involved in the mouse are also involved in humans and that further genetic and pathological studies of AHL in mice will add significantly to our understanding of presbycusis in humans. Our specific aims are to (1) formally test the hypothesis that a Cdh23 variant is responsible for the hearing loss attributed to the ahl locus by gene "knock-in" experiments and analyze the molecular mechanisms and interactions with other genes that underlie its effect on AHL;(2) refine the genetic map positions and attempt to identify the genes responsible for a/7/2, ah!4, and a/7/8; and (3) characterize the inner ear pathologies associated with the AHL loci and inbred mouse strains developed in Aims 1 and 2. The long-term objectives of this research are to identify the major genetic factors and molecular mechanisms that influence predisposition, time of onset, and pathological presentation of AHL in inbred strains of mice as models for human presbycusis. Relevance to public health. Presbycusis is the most common sensory deficit in human populations; about 1 in 3 adults older than 60 suffer from a significant hearing loss. The proposed genetic and pathological studies of age-related hearing loss in mice will provide important insights to improve our understanding of the major genetic factors and molecular pathways that influence human presbycusis, which could contribute to the development of diagnostics, preventive interventions, and therapies.

项目摘要。与年龄相关的听力损失（老年性耳聋）的遗传基础知之甚少 因为研究这种迟发性遗传复杂性疾病极其困难。这 实验室小鼠为研究人类老年性耳聋提供了有前景的模型，因为与年龄相关 听力损失（AHL）在近交系小鼠品系中很常见，并且小鼠更适合进行遗传分析。 我们已经证明 10 号染色体 (ahl) 上的基因是超过 10 种情况下 AHL 的主要易感因素 10 种近交系小鼠以及其他三个基因（ah!2、ah!4 和 a/7/8）以及线粒体突变 也会导致听力损失，特别是近交系。我们假设遗传倾向 小鼠中涉及的病理生理学途径也涉及人类，并且进一步 对小鼠 AHL 的遗传学和病理学研究将显着增进我们对老年性耳聋的理解 在人类中。我们的具体目标是 (1) 正式检验 Cdh23 变体负责的假设 通过基因“敲入”实验确定 ahl 基因座引起的听力损失并分析其分子机制 其对 AHL 影响的机制和与其他基因的相互作用；(2) 完善遗传图谱 位置并尝试识别负责 a/7/2、ah!4 和 a/7/8 的基因； (3) 表征 与目标 1 和 2 中开发的 AHL 基因座和近交小鼠品系相关的内耳病理。 这项研究的长期目标是确定主要的遗传因素和分子水平 影响近交系 AHL 易感性、发病时间和病理表现的机制 作为人类老年性耳聋模型的小鼠品系。 与公共卫生的相关性。老年性耳聋是人类最常见的感觉缺陷； 大约三分之一的 60 岁以上成年人患有严重的听力损失。建议的遗传和 对小鼠年龄相关性听力损失的病理研究将为改善我们的听力损失提供重要的见解。 了解影响人类老年性耳聋的主要遗传因素和分子途径， 这可能有助于诊断、预防干预和治疗的发展。