Genetics of Age-Related Hearing Loss

年龄相关性听力损失的遗传学

• 批准号: 6883932
• 负责人: KENNETH R JOHNSON
• 金额: $ 24.6万
• 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 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6883932
• 关键词: aging; cadherins; clinical research; complementary DNA; disease /disorder model; functional /structural genomics; gene complementation; gene expression; gene interaction; genetic polymorphism; genetic strain; genetic susceptibility; genetically modified animals; human old age (65+); human subject; laboratory mouse; linkage disequilibriums; pathologic process; phenotype; presbycusis; quantitative trait loci

DESCRIPTION (provided by applicant): Age-related hearing loss (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 genetic basis of 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 a mitochondrial mutation in A/J mice exacerbates this hearing loss. We hypothesize that the genetic predisposition and the pathophysiological pathways involved in the mouse are also involved in humans and that further genetic studies of AHL in mice will add significantly to our understanding of presbycusis in humans. Our specific aims are (1) to identify the Chr 10 Ahl gene, first analyzing Cdh23, a co-localized gene that is mutated in deaf waltzer mice, by genetic complementation tests for allelism and by gene rescue experiments; (2) to refine the map position of a newly discovered AHL locus on Chr 5 (Ahl2) and test candidate genes in the region; (3) to map additional loci that contribute to AHL and analyze defined locus combinations on uniform strain backgrounds; and (4) to test homologs of mouse AHL loci for their potential role in human presbycusis by analyses of linkage disequilibrium and DNA alterations in patients and matched controls. The long-term objectives of this research are to provide a better understanding of the molecular mechanisms and pathophysiology of AHL that could contribute to the development of diagnostics, preventive interventions, and therapies for human presbycusis.

描述（由申请人提供）：听力损失（老年性耳聋）是人群中最常见的感觉缺陷; 60岁以上的成年人中约有三分之一患有严重的听力损失。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疾病非常困难。实验室小鼠为研究人类老年性耳聋提供了有希望的模型，因为与年龄相关的听力损失（阿勒）在近交系小鼠中很常见，而且小鼠更适合遗传分析。我们已经证明，染色体10上的基因（阿勒）是超过10个近交系小鼠中AHL的主要易感因素，并且A/J小鼠中的线粒体突变加剧了这种听力损失。我们假设，遗传易感性和病理生理途径，涉及在小鼠中也涉及在人类和进一步的遗传研究阿勒小鼠将大大增加我们的理解，老年性耳聋在人类。我们的具体目标是：（1）通过等位基因互补试验和基因拯救实验，首先分析耳聋waltzer小鼠中突变的共定位基因Cdh 23，鉴定Chr 10阿勒基因：（2）精确定位Chr 5上新发现的AHL基因座（Ahl 2），并检测该区域的候选基因;（3）绘制有助于阿勒的额外基因座，并分析在统一品系背景下确定的基因座组合;（4）通过分析患者和匹配对照的连锁不平衡和DNA改变，测试小鼠阿勒基因座的同源物在人类老年性耳聋中的潜在作用。本研究的长期目标是更好地了解阿勒的分子机制和病理生理学，这可能有助于开发人类老年性耳聋的诊断、预防性干预和治疗方法。