Elucidation of Under-Investigated Biological Mechanisms of Age-Related Hearing Loss

阐明与年龄相关的听力损失的尚未研究的生物学机制

• 批准号: 9758848
• 负责人: Robert D Frisina
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9758848
• 关键词: Acoustics; Address; Affect; Age; Aging; Anatomy; Apoptosis; Apoptotic; Area; Arthritis; Atrophic; Auditory; Auditory system; Autophagocytosis; Biological; Biological Markers; Biological Response Modifier Therapy; CBA/CaJ Mouse; CRISPR/Cas technology; Carbamazepine; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cell Line; Cell physiology; Cells; Chronic; Clinical; Clinical Trials; Cochlea; Communication; Communication impairment; Data; Development; Disease; Down-Regulation; Etiology; Excision; Functional disorder; Future; Genes; Goals; Hearing; High Prevalence; Homeostasis; Human; Immune; Impairment; Inbred CBA Mice; Intervention; Ion Channel; Knockout Mice; Knowledge; Labyrinth; Lead; Light; Link; Lysosomes; Malignant Neoplasms; Measurement; Measures; Medical; Membrane; Metabolic; Microtubules; Molecular; Mus; Myopathy; Na(+)-K(+)-Exchanging ATPase; Nerve Degeneration; Nobel Prize; Organelles; Pathogenesis; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiological Processes; Presbycusis; Prevention; Process; Recycling; Research; Role; Sensory; Sodium-Potassium-Chloride Symporters; Son; Speech; Stress; Stria Vascularis; Structure; Testing; Training Programs; Transgenic Mice; Transgenic Organisms; Translational Research; age related; aged; aging population; base; cost; efficacy trial; experimental study; hearing impairment; hearing threshold; improved; in vitro Assay; in vivo; inhibition of autophagy; inhibitor/antagonist; innovation; insight; interest; mouse model; neurosensory; normal hearing; novel; permanent hearing loss; preclinical study; premature; prevent; programs; protein degradation; proteostasis; public health relevance; relating to nervous system; repaired; senescence; sound; spiral ganglion; vacuolar H+-ATPase; valproate; wasting; young adult

ABSTRACT This proposal will establish a proof-of-concept relating autophagy and age-related hearing loss (ARHL); which is a highly-prevalent communication and neurosensory disorder of our expanding aging population, affecting hundreds of millions worldwide, and costing billions of dollars annually for management and interventions. Clinical interventions are particularly challenging in many ways, because the mechanisms of ARHL are not clear. This proposal is highly innovative because it aims to carry out translational research for new breakthrough strategies, based upon links between age-related autophagy changes in the auditory system and the progression of ARHL. In ongoing experiments, we have found age-related accumulations of autophagy markers such as LC3 and p62 in the mammalian cochlea. Our in vivo turnover experiments showed that an autophagic flux stress may exist in autolysosomal formation steps. We also found that inhibition of autophagy flux decreased the membrane expressions of Na,K-ATPase (NKA) and sodium potassium chloride cotransporter (NKCC1) in the SV-cell line (SV-K1). These are the two key ion channels that maintain the endocochlear potential (EP) for normal hearing. Given our new findings, we hypothesis that aging may affect sensory, neural and metabolic aspects of the cochlea through age-related autophagic stress. Therefore, we propose to carry out step-by-step cellular mechanism studies to yield a comprehensive view of the role of autophagy in the aged cochlea. The aims of this proposal are threefold: First, we are going to determine whether autophagy stress is a general feature of hearing loss. Several autophagy inhibitors will be used to treat young adult CBA/CaJ mice and their hearing abilities and biomarker changes will be measured. Second, the functional roles of autophagy flux stress in the cochlea, including age-related apoptosis and SV-related ion channel activity will be investigated. Third, we will identify target step(s) in autophagic flux on which aging exerts influences in the cochlea, and explore original, feasible ways for future interventions for ARHL. This project is expected to provide novel insights into unknown areas of the biological mechanisms of ARHL, and resolve many of the mysteries that will not only fuel a better understanding of cochlear aging process, but will facilitate the development of more sophisticated and effective prevention and treatment options for ARHL.

抽象的 该提案将建立有关自噬和年龄相关性听力损失（ARHL）的概念验证；哪个 是我们不断扩大的老龄化人口中一种非常普遍的沟通和神经感觉障碍，影响着 全球有数亿人，每年用于管理和干预的费用达数十亿美元。 临床干预在很多方面都特别具有挑战性，因为 ARHL 的机制并不明确。 清除。该提案具有很强的创新性，因为它旨在针对新的领域开展转化研究。 突破性策略，基于听觉系统中与年龄相关的自噬变化和 ARHL 的进展。在正在进行的实验中，我们发现了与年龄相关的自噬积累 哺乳动物耳蜗中的 LC3 和 p62 等标记物。我们的体内周转实验表明 自噬流应激可能存在于自溶酶体形成步骤中。我们还发现自噬的抑制 通量降低了 Na,K-ATP 酶 (NKA) 和氯化钠钾的膜表达 SV 细胞系 (SV-K1) 中的协同转运蛋白 (NKCC1)。这是维持离子通道的两个关键离子通道。 正常听力的耳蜗内电位（EP）。鉴于我们的新发现，我们假设衰老可能会影响 通过与年龄相关的自噬应激来影响耳蜗的感觉、神经和代谢方面。因此，我们 建议开展逐步的细胞机制研究，以全面了解 衰老耳蜗中的自噬。该提案的目标有三个：首先，我们要确定 自噬应激是否是听力损失的一般特征。多种自噬抑制剂将被用于 治疗年轻的成年 CBA/CaJ 小鼠，并测量它们的听力能力和生物标志物变化。第二， 耳蜗自噬通量应激的功能作用，包括年龄相关的细胞凋亡和 SV 相关的离子 渠道活动将受到调查。第三，我们将确定衰老过程中自噬流的目标步骤 发挥对耳蜗的影响，为未来ARHL的干预探索原创、可行的方法。这 该项目预计将为 ARHL 生物学机制的未知领域提供新的见解，并且 解决许多谜团不仅有助于更好地了解耳蜗老化过程，而且将有助于 促进开发更复杂、更有效的 ARHL 预防和治疗方案。