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: 8803779
• 负责人: TOMAS ALBERTO PROLLA
• 金额: $ 37.42万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803779
• 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.

描述（由申请人提供）：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。人们对 AHL 的分子机制知之甚少，目前也没有已知的预防策略。我们最近表明，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核心参与者。我们和其他人还表明，热量限制 (CR) 是唯一已知能够延缓衰老和延长哺乳动物最大寿命的干预措施，它对某些 AHL 小鼠模型具有显着的抑制作用，而这种作用需要线粒体 Sirtuin Sirt3。 CR 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 中起着因果作用，并且 CR 会诱导耳蜗中 Sirt3 依赖性代谢变化，从而预防与年龄相关的线粒体功能障碍和 AHL。因此，本修订后的申请提出了旨在确定线粒体功能障碍在 AHL 小鼠模型中的作用和机制以及通过 CR 预防的实验。在具体目标 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 小鼠中进行的，因此我们建议在携带野生型 cdh23 基因座的两种 AHL 模型（B6.CAST+ahl 和 CBA/J）中测试 Bak 的作用。在具体目标 2 中，我们建议确定线粒体在 CR 介导的 AHL 预防中的作用和机制。这些研究将重点关注 Sirt3 的作用，及其增强氧化应激抵抗力和阻止 CR 响应线粒体凋亡的能力。