Genetics of Noise Resistance

抗噪音遗传学

• 批准号: 6915544
• 负责人: BRUCE L TEMPEL
• 金额: $ 56.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6915544
• 关键词: functional /structural genomics; gene expression; gene mutation; gene targeting; genetic susceptibility; laboratory mouse; microarray technology; noise biological effect; noise induced deafness; oligonucleotides; quantitative trait loci; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Noise-induced hearing loss (NIHL) and age-related hearing loss (AHL or presbycusis) are major health problems. They are common, their consequences are permanent, and their impacts on human communication and quality of life are significant. Although important advances have been made in characterizing the structural changes in the ear that are associated with NIHL or AHL, the mechanisms underlying these changes are poorly understood. In humans, hearing loss secondary to noise exposure is highly variable between individuals: some people have "tough" ears, while others have "tender" ears. In contrast to humans, laboratory mice show significantly less variability in NIHL among individuals within an inbred strain while there are striking differences in NIHL sensitivity between different inbred strains. Our long-term goal is to exploit these strain differences in mouse models to study the genetic factors influencing resistance and susceptibility to NIHL Here we propose to focus on the remarkable NIHL resistance observed in the inbred mouse strain 12986/SvEvTac (129S6). We will address the following Specific Aims: SA 1. Refine and confirm our preliminary Quantitative Trait Locus (QTL) map for NIHL resistance in 129S6. Develop a second NIHL-resistance QTL map in a different mouse strain, MOLF/Ei for comparison. SA 2: Generate congenic strains using both phenotype-driven selection for NIHL resistance and genotype-driven, marker-assisted selection for QTL regions. Isolated QTL regions will be tested for epistatic interactions. SA 3. Identify candidate NIHL resistance genes using DNA microarrays to study changes in gene expression after noise exposure. Genes differentially regulated between strains and mapping within QTL regions will be sequenced in both strains and compared for variations. SA 4. Strong candidate genes will be tested in genetic crosses to determine whether they interact functionally with the NIHL-resistant QTL. Nucleotide differences in genes suspected to account for the QTL will be tested using gene targeting knock-in techniques to see if they are sufficient to transfer NIHL resistance to another strain. The characterization of genes influencing NIHL resistance will provide fundamental insight into the cellular and molecular processes underlying noise-induced cochlear damage. In turn, these insights will be key to devising effective strategies to preserve hearing in human populations.

描述（由申请人提供）：噪声引起的听力损失（NIHL）和与年龄有关的听力损失（AHL或Presbycusis）是主要的健康问题。它们很普遍，后果是永久的，它们对人类交流和生活质量的影响很大。尽管在表征与NIHL或AHL相关的耳朵的结构变化方面取得了重要的进步，但这些变化的机制知之甚少。在人类中，噪声暴露继发的听力损失之间是个人之间的高度变化：有些人的耳朵“坚韧”，而另一些人则具有“温柔”的耳朵。与人类相反，实验室小鼠在近交菌株中的个体中NIHL的变异性明显降低，而不同近交菌株之间NIHL敏感性的差异显着。我们的长期目标是利用小鼠模型中的这些应变差异，以研究影响抗药性和对NIHL易感性的遗传因素，我们建议将重点放在近近交小鼠菌株12986/sVEVTAC中观察到的显着NIHL抗性（129S6）。我们将解决以下特定目的：SA 1。完善并确认我们的初步定量性状基因座（QTL）图中的NIHL电阻在129S6中。在不同的小鼠菌株MOLF/EI中开发第二个NIHL抗性QTL图，以进行比较。 SA 2：使用表型驱动的NIHL抗性和基因型驱动的，标记辅助选择的QTL区域的选择。孤立的QTL区域将进行上皮相互作用的测试。 SA 3。使用DNA微阵列确定候选NIHL抗性基因，以研究噪声暴露后基因表达的变化。 QTL区域内菌株和映射的差异调节的基因将在两种菌株中进行测序，并比较变化。 SA4。强候选基因将在遗传杂交中进行测试，以确定它们是否与NIHL耐药QTL的功能相互作用。怀疑考虑到QTL的基因的核苷酸差异将使用靶向敲击技术进行测试，以查看它们是否足以将NIHL耐药性转移到另一个菌株中。影响NIHL耐药性的基因的表征将提供对噪声诱导的耳蜗损伤的细胞和分子过程的基本见解。反过来，这些见解将是制定有效策略来保存人口听力的关键。