STRESS PATHWAYS IN THE AGING COCHLEA

可诱导的应激反应首先在果蝇中被发现为“热休克”反应， 但现在已知它是一种普遍存在且高度保守的诱导机制，以保护细胞免受各种破坏性生理和环境应激。在哺乳动物中，该途径通过热休克转录因子1（Hsf 1）的活化来调节，所述热休克转录因子1诱导热休克蛋白（Hsps）。这个项目是基于证据，无论是从已发表的研究和我们的初步数据，即诱导应激反应在老龄动物减少。该提案的总体假设是，老年动物耳蜗的应激反应系统同样受到损害，使感觉细胞更容易受到压力，从而导致细胞死亡，导致年龄相关性听力损失（ARHL）。目标1中的研究将使用CBA小鼠 在他们的大部分寿命中听力正常，以研究在两种压力（热和噪音）下诱导应激反应的年龄相关性下降。目标2将研究以下假设：随着年龄的增长，应激反应途径的减少将反映在从噪声暴露中恢复的能力下降，该噪声暴露仅导致野生型小鼠的暂时性听力损失。目标3中的研究将检验以下假设：消除Hsf 1基因敲除小鼠的应激反应将影响年龄相关性听力损失的发生率或严重程度。目标4中的研究与项目0001中的研究相结合，将检验以下假设： 防御和诱导应激反应导致年龄相关性听力损失。从8个月开始，将Hsf 1基因敲除小鼠及其野生型同窝小鼠维持在添加氧化剂的饮食中，以检测抗氧化剂对ARHL和应激反应的影响。目的5将产生和表征另外两种在耳蜗中表达组成型活性形式的HSF 1的转基因小鼠模型。这些研究的诱导应激反应在老化的耳蜗将提供一个更好的理解的作用，这一重要的保护途径在ARHL，并将提供一个合理的基础，为未来的干预措施，以预防和/或治疗老年性耳聋。

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.