The Role of Glutathione Reductase in Age-related Hearing Loss

描述（由申请人提供）：众所周知，在没有营养不良的情况下减少25-60%的食物消耗，可以持续延长各种物种的平均寿命和最长寿命。热量限制（CR）还可以延缓各种年龄相关疾病的进展，如哺乳动物衰老的常见特征——年龄相关性听力损失（AHL）。先前的研究表明，CR减缓了CBA/J小鼠AHL的进展，而我们之前的研究表明，CR延缓了C57BL/6J小鼠AHL的发病，减少了耳蜗细胞的损失。了解CR的作用机制是衰老研究的核心领域，因为它可能会产生新的治疗衰老和年龄相关疾病的方法。然而，CR预防AHL的分子机制在很大程度上仍然未知。我的主要假设是抗氧化酶谷胱甘肽还原酶（Gsr）在老化和CR条件下保护内耳免受氧化应激和减缓AHL的发展方面起着重要作用。因此，本研究将确定Gsr在哺乳动物AHL中的作用和分子机制。在Specific Aim 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)保护小鼠内耳免受氧化应激并减缓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Specific Aim 2中，我提议确定在CR条件下，Gsr是否在以下方面发挥重要作用：1)减少内耳氧化应激和预防AHL； 2)增强内耳谷胱甘肽系统。本研究将促进对哺乳动物听觉系统中CR抗衰老作用的基本分子机制的理解。

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.