The Role of Glutathione Reductase in Age-related Hearing Loss

描述（由申请人提供）：众所周知，减少25 - 60%的食物消耗而不营养不良可持续延长各种物种的平均寿命和最长寿命。热量限制（CR）也延缓了各种年龄相关疾病的进展，如年龄相关性听力损失（AHL），这是哺乳动物衰老的一个常见特征。先前的研究已经表明，CR减缓CBA/J小鼠中AHL的进展，而我们先前已经表明，CR延迟C57 BL/6J小鼠中AHL的发作并减少耳蜗细胞损失。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年龄相关疾病提供新的治疗方法。然而，CR预防AHL的分子机制仍不清楚。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衰老过程中AHL的发展和CR条件下起着至关重要的作用。因此，本研究将确定Gsr在哺乳动物AHL中的作用及其分子机制。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和减缓小鼠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）减少内耳中的氧化应激和预防AHL; 2）增强内耳中的谷胱甘肽系统。这项研究将促进对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。

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.