The Role of Glutathione Reductase in Age-related Hearing Loss

描述(由申请人提供)：公认的是，在不营养不良的情况下将食物消耗量减少25%-60%，持续延长各种物种的平均和最长寿命。卡路里限制(CR)还可以延缓多种与年龄相关的疾病的进展，如哺乳动物的年龄相关性听力损失(AHL)，这是衰老的一个常见特征。先前的一项研究表明，CR延缓了CBA/J小鼠AHL的进展，而我们之前已经证明，CR推迟了C57BL/6J小鼠AHL的发生，并减少了耳蜗细胞的损失。了解CR的作用机制是衰老研究的中心领域，因为它可能为衰老和与年龄相关的疾病提供新的治疗方法。然而，CR预防AHL的分子机制在很大程度上仍不清楚。我的中心假设是，抗氧化酶谷胱甘肽还原酶(GSR)在保护内耳免受氧化应激和减缓AHL在老化和CR条件下的发展方面起着至关重要的作用。因此，这项拟议的研究将确定GSR在哺乳动物AHL中的作用和分子机制。在具体目标1中，我建议确定在衰老过程中，GSR是否在以下方面发挥重要作用：1)保护内耳免受氧化应激，减缓小鼠AHL的发展；2)在基础饮食条件下维持适当的谷胱甘肽抗氧化防御。在具体目标2中，我建议确定在CR条件下，GSR是否在以下方面发挥重要作用：1)减少内耳的氧化应激，预防AHL；2)增强内耳的谷胱甘肽系统。这项拟议的研究将促进对CR在哺乳动物听觉系统中抗衰老作用的基本分子机制的理解。 公共卫生相关性：年龄相关性听力损失(AHL)是哺乳动物衰老的常见特征，也是老年人群中最常见的感觉障碍。本项目的主要目的是确定抗氧化酶谷胱甘肽还原酶在急性淋巴细胞性白血病中的作用和分子机制。对这些分子机制的了解对通过发现/开发治疗人类AHL和其他与年龄相关的感觉障碍的新疗法来改善健康结果具有巨大的潜力。

DESCRIPTION (provided by applicant): It is well established that reducing food consumption by 25-60% without malnutrition consistently extends both the mean and maximum lifespan of a variety of species. Caloric restriction (CR) also delays the progression of a variety of age-associated diseases such as age-related hearing loss (AHL), a common feature of aging, in mammals. A previous study has shown that CR slows the progression of AHL in CBA/J mice, while we have shown previously that CR delays the onset of AHL in C57BL/6J mice and reduces cochlear cell loss. Understanding the mechanism of action of CR is a central area of aging research, since it is likely to yield novel therapeutic approaches for aging and age-related related diseases. Yet, the molecular mechanisms underlying AHL prevention by CR remain largely unknown. My central hypothesis is that the antioxidant enzyme glutathione reductase (Gsr) plays an essential role in protecting the inner ear from oxidative stress and slowing the development of AHL during aging and under CR conditions. Therefore, this proposed study will determine the role and the molecular mechanisms of Gsr in AHL in mammals. In Specific Aim 1, I propose to determine whether during aging, Gsr plays an essential role in: 1) protection of the inner ear from oxidative stress and slowing the development of AHL in mice and 2) maintenance of the appropriate glutathione antioxidant defense under basal diet conditions. In Specific Aim 2, I propose to determine whether under CR conditions, Gsr plays an essential role in: 1) reduction of oxidative stress in the inner ear and prevention of AHL and 2) enhancement of the glutathione system in the inner ear. This proposed study will advance understanding of the fundamental molecular mechanisms underlying the anti-aging action of CR in the auditory system in mammals. PUBLIC HEALTH RELEVANCE: Age-related hearing loss (AHL) is a common feature of mammalian aging and is the most frequently occurring sensory disorder in the elderly population. The main goal of this proposed project is to determine the role and the molecular mechanisms of the antioxidant enzyme glutathione reductase in AHL. Knowledge of these molecular mechanisms has enormous potential for improving health outcomes through the discovery/development of novel therapeutics for human AHL and other age-related sensory disorders.