GENETIC ANALYSIS OF STRESS RESISITANCE /LOSS OF HEARING

这个项目的重点是分析遗传控制和生理调节器，这些因素调节了遗传异质性小鼠群体中的听力损失。试验种群将由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一只小鼠在基因上都是独一无二的，并且是种群中每一种动物的完全同胞。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。在600只小鼠中，有一半将在14.5个月大时暴露在噪音诱导的耳蜗损伤中。基于SNP的 300个基因座的基因分型将提供调节听力的基因座的基因组图谱，其 随着年龄的变化，以及其对噪声引起的损害的抵抗力(目标1)。目的2将使用来自每个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应激的抗性的个体差异有关并可预测的假设。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包括成纤维细胞在内的多种细胞类型的应激敏感性来实现的。目的3将验证一种假设，即调节功能性听力损失和细胞应激抵抗的基因，以及潜在的非遗传因素，也会影响耳蜗毛细胞的丢失和对耳蜗结构的氧化损伤。目的4检验一系列关于早期生长、成熟和激素模式对中老年应激抵抗和功能结果(包括听力损失)的影响的相关假说。目的5将测量一系列年龄敏感的特征，包括免疫和视觉功能指数，以检验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的假设。作为一个有用的副产品，这一策略还将产生大量关于调节小鼠和老年小鼠的生长、成熟、抗应激、白内障、激素和免疫的基因座的遗传信息。选择的方法将允许全面评估与年龄相关的听力变化在多大程度上受到遗传、细胞和荷尔蒙因素的影响，这些因素对小鼠的衰老过程进行了计时。

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.