GENETIC ANALYSIS OF STRESS RESISITANCE /LOSS OF HEARING

该项目的重点是分析调节遗传异质性小鼠群体听力损失的遗传控制和生理调节因子。试验群体将由600只作为（CAST/Ei X 129 S1/SvImJ）F1雌性和（C3 H/HeJ X FVB/NJ）F1雄性后代繁殖的动物组成。在这种四向杂交中产生的每只小鼠在遗传上都是独特的，并且是种群中每只动物的全同胞。在2、8、14、18和22月龄时，通过听觉脑干反应测试每只小鼠的听力敏锐度。600只小鼠中的一半将在14.5个月大时暴露于噪声诱导的耳蜗损伤。基于snp 在300个基因座中的每一个上进行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 随着年龄的变化，以及其对噪音引起的损害的抵抗力（目标1）。目的2将使用来自每只受试小鼠的成纤维细胞系的体外分析，检验听力损失与细胞对氧化细胞毒性应激的耐受性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，即延缓衰老和延长小鼠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。目的3将检验这样的假设，即调节功能性听力损失和细胞应激抵抗力的基因和潜在的非遗传因素也影响耳蜗毛细胞损失和耳蜗结构的氧化损伤。目的4测试一系列有关早期生命生长、成熟和激素模式对中年和晚年应激抵抗力和功能结果（包括听力损失）的影响的相关假设。目标5将测量一系列年龄敏感性特征，包括免疫力和视觉功能指数，以检验年龄相关性听力损失的个体间差异与小鼠衰老多个方面的差异有关的假设。这种策略还将产生一个有用的副产品，即关于调节年轻和老年小鼠生长、成熟、抗应激、白内障、激素和免疫力的基因座的大量遗传信息。所选择的方法将允许全面评估听力中年龄依赖性变化的程度，这些变化是由遗传，细胞和激素因素塑造的，这些因素决定了小鼠的衰老过程。

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.