STRESS PATHWAYS IN THE AGING COCHLEA

老化耳蜗的压力通路

• 批准号: 6966783
• 负责人: MARGARET I. LOMAX
• 金额: $ 26.19万
• 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/6966783
• 关键词: aging; antioxidants; chemoprevention; cochlea; diet therapy; dietary supplements; environmental stressor; genetic manipulation; genetically modified animals; heat shock proteins; heat stimulus; immunocytochemistry; in situ hybridization; laboratory mouse; noise; nonhuman therapy evaluation; nutrition related tag; pathologic process; physiologic stressor; presbycusis; protein structure function; stress

The inducible stress response was first discovered as a "heat shock" response in Drosophila, but is now known to be a ubiquitous and highly conserved inducible mechanism to protect cells from various damaging physiological and environmental stresses. In mammals, this pathway is regulated through the activation of heat shock transcription factor 1 (Hsf 1), which induces heat shock proteins (Hsps). This project is based on evidence, both from published studies and from our preliminary data, that the inducible stress response decreases in aging animals. The overall hypothesis of this proposal is that the stress response system of the cochlea is similarly compromised in aged animals, making the sensory cells more vulnerable to stress and hence to cell death, leading to age-related hearing loss (ARHL). Studies in Aim 1 will use CBA mice with normal hearing throughout most of their lifespan to investigate the age-related decrease in the inducible stress response following two stresses: heat and noise. Aim 2 will investigate the hypothesis that the decrease in the stress response pathway with aging will be reflected in a decrease in the ability to recover from a noise exposure that causes only temporary hearing loss in wild-type mice. Studies in Aim 3 will test the hypothesis that eliminating the stress response in Hsf1 null mice will affect the rate or severity of age-related hearing loss. Studies in Aim 4, which interface with studies in Project 0001, will test the hypothesis that both antioxidant defenses and the inducible stress response contribute to age-related hearing loss. Hsf1 null mice and their wild-type littermates will be maintained on an oxidant-supplemented diet from 8 months to test the effect of antioxidants on ARHL and the stress response. Aim 5 will generate and characterize two additional transgenic mouse models that express a constitutively active form of HSF1 in the cochlea. These studies of the inducible stress response in the aging cochlea will provide a better understanding of the role of this important protective pathway in ARHL and will provide a rational basis for future interventions to prevent and/or treat presbycusis.

这种可诱导的应激反应首先在果蝇身上被发现是一种“热休克”反应， 但现在已知是一种普遍存在的高度保守的诱导机制，可以保护细胞免受各种破坏性的生理和环境压力的影响。在哺乳动物中，这一途径是通过热休克转录因子1(HSF 1)的激活来调节的，热休克转录因子1诱导热休克蛋白(HSPs)。这个项目是基于来自已发表的研究和我们的初步数据的证据，即在老年动物中可诱导的应激反应减少。这一建议的总体假设是，老年动物耳蜗的应激反应系统类似地受到损害，使感觉细胞更容易受到应激，从而导致细胞死亡，导致年龄相关性听力损失(ARHL)。AIM 1的研究将使用CBA小鼠 在他们大部分的一生中听力正常，以调查在两种压力下诱导的应激反应与年龄相关的下降：热和噪音。目的2将研究一种假设，即随着年龄的增长，应激反应途径的减少将反映为从噪声暴露中恢复的能力下降，而噪声暴露只会导致野生型小鼠的暂时性听力损失。Aim 3的研究将验证这样的假设，即消除HSF1基因缺失小鼠的应激反应将影响与年龄相关的听力损失的速度或严重程度。Aim 4中的研究将与Project 0001中的研究相结合，将检验这两种抗氧化剂都 防御和诱导的应激反应会导致与年龄相关的听力损失。HSF1基因缺失的小鼠和它们的野生型小鼠将在8个月内保持添加氧化剂的饮食，以测试抗氧化剂对ARHL和应激反应的影响。Aim 5将产生并鉴定另外两个转基因小鼠模型，它们在耳蜗中表达一种构成活性形式的HSF1。这些研究将有助于更好地了解这一重要的保护途径在ARHL中的作用，并为今后预防和/或治疗老年性耳聋的干预提供合理的依据。