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

基本信息

批准号：
9014535
负责人：
TOMAS ALBERTO PROLLA
金额：
$ 36.76万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9014535
关键词：
Affect Age-Years Aging Aging-Related Process Alleles Apoptosis Apoptotic CBA/CaJ Mouse CDH23 gene 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 improved interest mitochondrial dysfunction mouse model novel novel strategies prevent research study response therapeutic target

Affect Age-Years Aging Aging-Related Process Alleles Apoptosis Apoptotic CBA/CaJ Mouse CDH23 gene 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 improved interest mitochondrial dysfunction mouse model novel novel strategies prevent research study response therapeutic target

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项目摘要

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）：与年龄相关的听力损失（AHL，也称为Presbycusis）是哺乳动物衰老的普遍特征，是老年人群中最常见的感觉障碍。 AHL的分子机制知之甚少，目前尚无已知的预防策略。我们最近表明，B6小鼠中的AHL可以通过pro凋亡基因BAK的突变来预防，这是细胞凋亡的线粒体途径中的核心参与者。我们和其他人还表明，热量限制（CR）是延迟衰老并延长哺乳动物最大寿命的唯一干预措施，对某些AHL的某些小鼠模型具有明显的抑制作用，并且这种效应需要线粒体Sirtuin Sirt3。 CR可提高线粒体功能，减少耳蜗中的氧化应激，并防止与年龄相关的耳蜗凋亡。我们的中心假设是线粒体功能障碍在AHL中起因果作用，并且CR在耳蜗中诱导SIRT3依赖性代谢转移，从而阻止与年龄相关的线粒体功能障碍和AHL。因此，该修订后的应用提出了旨在建立AHL小鼠模型中线粒体功能障碍及其预防CR的作用和机制的实验。在特定目标1中，我们建议确定BAK介导的线粒体凋亡在AHL中的作用。由于我们先前的研究是在带有CDH23突变的B6小鼠中进行的，因此我们建议测试BAK在携带野生型CDH23基因座的AHL模型中的作用，B6.cast+AHL和CBA/J。在特定目标2中，我们建议确定线粒体在CR介导的AHL预防中的作用和机理的作用。这些研究将集中在SIRT3的作用上，及其增加氧化应激抗性和阻断线粒体凋亡的能力，以响应CR。