GENETIC ANALYSIS OF STRESS RESISITANCE /LOSS OF HEARING

抗应激/听力损失的遗传分析

• 批准号: 6966784
• 负责人: RICHARD A MILLER
• 金额: $ 27.49万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6966784
• 关键词: aging; animal old age; cochlea; cytotoxicity; environmental stressor; family genetics; gene mutation; genetic mapping; genetic polymorphism; genetic susceptibility; genetically modified animals; genotype; hearing; hormone regulation /control mechanism; immature animal; laboratory mouse; longevity; longitudinal animal study; mature animal; noise; oxidative stress; presbycusis; quantitative trait loci; stress

This project focuses on analysis of the genetic controls and physiological regulators that modulate hearing loss in a population of genetically heterogeneous mice. The test population will consist of 600 animals bred as the progeny of (CAST/Ei X 129S1/SvImJ)F1 females and (C3H/HeJ X FVB/NJ)F1 males. Each mouse generated in this four-way cross is genetically unique, and a full sib to each other animal in the population. Each mouse will be tested for hearing acuity by auditory brainstem response at ages 2, 8, 14, 18 and 22 months. Half of the 600 mice will be exposed to noise-induced cochlear injury at age 14.5 months. SNP-based genotyping at each of 300 loci will provide a genomic map of loci modulating hearing acuity, its change over age, and its resistance to noise-induced damage (Aim 1). Aim 2 will test the hypothesis that hearing loss is related to, and predictable by, individual differences in cellular resistance to oxidative cytotoxic stress, using in vitro analyses of fibroblast cell lines from each tested mouse. This strategy reflects recent evidence that mutations that retard aging and extend life span in mice may do so by alterations of stress-sensitivity in multiple cell types, including fibroblasts. Aim 3 will test the hypothesis that the genes, and potentially the non-genetic factors, that modulate functional hearing loss and cellular stress resistance also affect cochlear hair cell loss and oxidative damage to cochlear structures. Aim 4 tests a series of related hypothesis concerning the effects of early-life growth, maturation, and hormone patterns on mid- and late-life stress resistance and functional outcome, including hearing loss. Aim 5 will measure a range of age-sensitive traits, including indices of immunity and visual function, to test the hypothesis that inter-individual differences in age-related hearing loss are linked to differences among mice in multiple aspects of aging. This strategy will also yield, as a useful byproduct, a great deal of genetic information about loci that modulate growth, maturation, stress resistance, cataracts, hormones, and immunity in young and older mice. The approach chosen will permit a comprehensive assessment of the extent to which age-depending alterations in hearing are molded by genetic, cellular and hormonal factors that time the aging process in mice.

该项目重点分析调节遗传异质小鼠群体听力损失的遗传控制和生理调节因子。测试群体将由 600 只动物组成，它们是 (CAST/Ei X 129S1/SvImJ)F1 雌性和 (C3H/HeJ X FVB/NJ)F1 雄性的后代。在这种四向杂交中产生的每只小鼠在基因上都是独一无二的，并且是种群中其他动物的完整同胞。每只小鼠将在 2、8、14、18 和 22 个月大时通过听觉脑干反应测试听力敏锐度。 600 只小鼠中有一半会在 14.5 个月大时遭受噪音引起的耳蜗损伤。基于SNP的 对 300 个基因座中每一个的基因分型将提供调节听力敏锐度的基因座的基因组图谱，其 随着年龄的增长而变化，及其对噪声引起的损害的抵抗力（目标 1）。目标 2 将通过对每只测试小鼠的成纤维细胞系进行体外分析，检验听力损失与细胞对氧化细胞毒性应激的抵抗力的个体差异相关并可通过其预测的假设。这一策略反映了最近的证据，即延缓小鼠衰老和延长寿命的突变可能是通过改变多种细胞类型（包括成纤维细胞）的应激敏感性来实现的。目标 3 将检验以下假设：调节功能性听力损失和细胞应激抵抗的基因和潜在的非遗传因素也会影响耳蜗毛细胞损失和耳蜗结构的氧化损伤。目标 4 测试了一系列相关假设，涉及生命早期的生长、成熟和激素模式对中晚年抗压能力和功能结果（包括听力损失）的影响。目标 5 将测量一系列年龄敏感特征，包括免疫和视觉功能指数，以检验以下假设：与年龄相关的听力损失的个体间差异与小鼠在衰老的多个方面的差异有关。作为有用的副产品，该策略还将产生大量关于调节年轻和年长小鼠的生长、成熟、抗应激、白内障、激素和免疫力的基因座的遗传信息。所选择的方法将允许对遗传、细胞和激素因素影响小鼠衰老过程的年龄依赖性听力变化的程度进行全面评估。