The Role of mitochondria in Age-Related Hearing Loss

线粒体在年龄相关性听力损失中的作用

• 批准号: 8292770
• 负责人: TOMAS ALBERTO PROLLA
• 金额: $ 44.2万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292770
• 关键词: Affect; Age-Years; Aging; Aging-Related Process; Alleles; Apoptosis; Apoptotic; CBA/CaJ Mouse; Caloric Restriction; Cell Death; Cell physiology; Cells; Cochlea; Development; Disease; Elderly; Genes; Genetic; Goals; Hair Cells; Half-Life; Hearing; Hearing Aids; Human; Intervention; Labyrinth; Longevity; Mammals; Measurement; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Mouse Strains; Mus; Mutation; NADP; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Play; Population; Presbycusis; Prevention; Prevention strategy; Preventive; Process; Reporting; Resistance; Role; Sensory Disorders; Stress; Testing; Therapeutic; age related; design; effective therapy; exon skipping; human CDH23 protein; improved; interest; mitochondrial dysfunction; mouse model; novel; novel strategies; prevent; research study; response; therapeutic target

DESCRIPTION (provided by applicant): Age-related hearing loss (AHL, also known as presbycusis) is a universal feature of mammalian aging and is the most common sensory disorder in the elderly population. Molecular mechanisms of AHL are poorly understood, and there are currently no known preventive strategies. We have recently shown that AHL in B6 mice can be prevented by a mutation in the pro-apoptotic gene Bak, a central player in the mitochondrial pathway of apoptosis. We and others have also shown that caloric restriction (CR), the only intervention known to retard aging and extend maximum lifespan in mammals, has a marked inhibitory effect on some mouse models of AHL, and that this effect requires the mitochondrial sirtuin Sirt3. CR improves mitochondrial function, reduces oxidative stress in the cochlea, and prevents age-related cochlear apoptosis. Our central hypothesis is that mitochondrial dysfunction plays a causal role in AHL, and that CR induces Sirt3-dependent metabolic shifts in the cochlea that prevent age-related mitochondrial dysfunction and AHL. Thus, this revised application proposes experiments designed to establish the role and mechanisms of mitochondrial dysfunction in mouse models of AHL and its prevention by CR. In Specific Aim 1, we propose to determine the role of Bak-mediated mitochondrial apoptosis in AHL. Because our previous studies have been performed in B6 mice that carry a cdh23 mutation, we propose to test the role of Bak in two models of AHL that carry a wild-type cdh23 locus, B6.CAST+ahl and CBA/J. In Specific Aim 2 we propose to determine the role of and mechanism of mitochondria in the CR-mediated prevention of AHL. These studies will focus on the role of Sirt3, and its ability to increase oxidative stress resistance and block mitochondrial apoptosis in response to CR. PUBLIC HEALTH RELEVANCE: Age-related hearing loss (AHL) is a major disorder of the elderly, affecting a large segment of the population. The main goal of the proposed studies is to determine the role of mitochondria in AHL, with a focus in two genes, Bak and Sirt3. These studies will generate novel opportunities for therapeutic approaches to AHL.

描述(申请人提供)：年龄相关性听力损失(AHL，也称为老年性耳聋)是哺乳动物衰老的普遍特征，也是老年人群中最常见的感觉障碍。AHL的分子机制尚不清楚，目前尚无已知的预防策略。我们最近已经证明，B6小鼠的AHL可以通过促凋亡基因Bak的突变来预防，Bak是线粒体凋亡途径的中心参与者。我们和其他人还表明，卡路里限制(CR)是已知的唯一可以延缓哺乳动物衰老和延长最长寿命的干预措施，对某些AHL小鼠模型有显著的抑制作用，并且这种效果需要线粒体sirtuin SIRT3。CR可改善线粒体功能，减少耳蜗氧化应激，并防止与年龄相关的耳蜗细胞凋亡。我们的中心假设是线粒体功能障碍在AHL中起到了因果作用，CR诱导了SIRT3依赖的耳蜗代谢改变，从而防止了年龄相关性线粒体功能障碍和AHL。因此，这项修订的申请提出了旨在建立线粒体功能障碍在小鼠AHL模型中的作用和机制以及CR对其预防的实验。在特定的目标1中，我们建议确定Bak介导的线粒体凋亡在AHL中的作用。由于我们之前的研究是在携带CDH23突变的B6小鼠身上进行的，因此我们建议在两种携带野生型CDH23基因的AHL模型B6.CAST+AHL和CBA/J中测试Bak的作用。这些研究将集中在SIRT3的作用，以及它在CR反应中增强氧化应激抵抗和阻止线粒体凋亡的能力。 公共卫生相关性：年龄相关性听力损失(AHL)是老年人的一种主要疾病，影响到很大一部分人口。拟议研究的主要目标是确定线粒体在AHL中的作用，重点是两个基因，Bak和SIRT3。这些研究将为AHL的治疗方法创造新的机会。