Project 1: Identification of susceptibility genes for age-related hearing loss

项目1：年龄相关性听力损失易感基因鉴定

• 批准号: 10018498
• 负责人: BRAD SCHULTE
• 金额: $ 35.3万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10018498
• 关键词: Acoustic Nerve; Address; African; Age; Age of Onset; Age-Years; Aging; Algorithms; Alleles; Animal Model; Auditory; Bioinformatics; Biological; Biological Assay; Candidate Disease Gene; Categories; Characteristics; Clinical Research; Cochlea; Cognitive; Complex; Consent; Coupled; DNA; Data; Databases; Development; Diagnostic tests; Dideoxy Chain Termination DNA Sequencing; Disease; Ear; Elderly; Environmental Risk Factor; Etiology; European; Genes; Genetic; Genetic study; Genetically Engineered Mouse; Genotype; Goals; Hearing Tests; Heritability; High Prevalence; Human; Individual; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Laboratories; Labyrinth; Lateral; Left; London; Measures; Medical; Metabolic; Molecular; Molecular Genetics; Morphology; Mus; Mutant Strains Mice; Mutation; Nature; Noise; Organ of Corti; Paraffin; Pathogenicity; Pathologic; Pathway interactions; Pattern; Phenotype; Physiological; Play; Population; Predisposition; Preparation; Presbycusis; Prevalence; Prevention; Process; Proteins; Protocols documentation; Public Health; Recording of previous events; Resolution; Review Literature; Role; Sampling; Scanning Electron Microscopy; Sensory; Severities; Steel; Stress; Susceptibility Gene; Techniques; Temporal bone structure; Tissues; Variant; age related; aged; animal data; base; causal variant; cohort; college; common treatment; confocal imaging; exome; exome sequencing; experimental study; gene product; gene therapy; genetic analysis; genetic risk factor; genetic variant; genome wide association study; genome-wide; hearing impairment; hearing loss phenotype; high risk; human morbidity; human subject; longitudinal database; microscopic imaging; mouse model; next generation sequencing; normal hearing; novel diagnostics; novel strategies; novel therapeutics; population based; programs; recruit; screening; social; therapy development; tool

PROJECT SUMMARY/ABSTRACT – PROJECT 1 Age-related hearing loss (presbyacusis) is a consequence of accumulated environmental stresses to the inner ear and an intrinsic genetically controlled aging process, with as much as 60% of hearing loss in older adults attributable to heritability. The often uncertain medical and noise exposure histories in human subjects coupled with the high variability in the age of onset, rate of progression and the nature and severity of the hearing loss make it difficult to attribute presbyacusis to a specific cause. Moreover, this phenotypic variability and other characteristics strongly suggest that age-related hearing loss is a complex polygenic disorder possibly involving different alleles on multiple genes, although in some instances, it could result from a mutation(s) in a single gene. Advances in next generation sequencing have provided a powerful new tool to address the genetic basis of many age-related diseases. Here we continue to investigate the genetic, molecular and cellular basis of human presbyacusis. Project 1 takes advantage of the Center's extensive and continuously growing database (Core B) containing well documented medical and noise exposure histories and auditory function measures along with DNA samples from large numbers of human subjects. It also capitalizes on the development of new algorithms based on audiograms and data from animal models to define specific age-related hearing loss phenotypes in our subjects. Accordingly, we will perform a comprehensive population-based cohort molecular genetic study to provide information about genetic contributions to specific auditory phenotypes and biological pathways involved with age-related hearing loss. Aim 1.1 continues to identify and validate genetic variants associated with increased susceptibility to presbyacusis by employing molecular genetic analyses using whole exome sequence data from a replication cohort of ≥55 year old subjects of non-Finnish European ancestry and an African ancestry cohort. This aim will also investigate causal relationships between specific genetic variants and hearing loss via functional and histopathological analyses of mouse lines generated by knock-in or knock-out of specific candidate genetic variants. Aim 1.2 determines the pathological and potential functional consequences of genetic variants causing age-related hearing loss by assessing the distribution and changes in the expression pattern of promising candidate gene products and their association with pathological changes in human temporal bones.

项目摘要/摘要 - 项目1 与年龄相关的听力损失（长期）是累积环境压力的结果 内耳和固有控制的衰老过程，年龄较大的听力损失多达60％ 归因于遗传力的成年人。在人类受试者中经常不确定的医学和噪音暴露历史 加上发病年龄，进展速度和性质和严重程度的高度差异 听力损失使得将长老会归因于特定原因变得困难。而且，这种表型变异性 其他特征强烈表明与年龄相关的听力损失是一种复杂的多基因障碍 在多个基因上涉及不同等位基因的可能性，尽管在某些情况下可能是由 单个基因中的突变。下一代测序的进步为 解决许多与年龄有关的疾病的遗传基础。在这里，我们继续研究遗传， 人类长老会的分子和细胞基础。项目1利用中心的广泛和 持续增长的数据库（核心B），其中包含有记录良好的医学和噪声曝光历史 和听觉功能以及来自大量人类受试者的DNA样本。也是如此 根据基于听力图和来自动物模型的数据的数据来开发新算法的开发 我们受试者中与年龄相关的特定听力损失表型。根据，我们将进行全面的 基于人群的队列分子遗传研究，以提供有关特定遗传贡献的信息 听觉表型和与年龄有关的听力损失涉及的生物途径。 AIM 1.1继续 通过采用使用和验证与长期易感性相关的遗传变异 分子遗传分析使用来自≥55岁的复制队列中的整个外显子组序列数据 非本土欧洲血统和非洲血统队列的主题。这个目标也将调查 特定遗传变异和通过功能病理学的听力丧失之间的因果关系 通过特定候选遗传变异的敲入或敲除产生的小鼠线的分析。目标1.2 确定引起年龄相关的遗传变异的病理和潜在功能后果 通过评估承诺候选基因的表达模式的分布和变化来听力损失 产品及其与人类临时骨骼中病理变化的关联。