Mechanisms of Biological Aging of Cochlear Hair Cells

耳蜗毛细胞的生物衰老机制

• 批准号: 9612658
• 负责人: Zhi-Zhou He
• 金额: $ 39.13万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9612658
• 关键词: Address; Adult; Aging; Antisense Oligonucleotides; Apical; Apoptosis; Apoptotic; Auditory; Bilateral; Bioinformatics; Biological; Biological Aging; Biological Markers; CBA/J Mouse; Cell Aging; Cell Death; Cell physiology; Cellular Morphology; Cellular Structures; Cochlea; Confocal Microscopy; Down-Regulation; Electron Microscopy; Electrophysiology (science); Exhibits; Future; Gene Expression; Gene Proteins; Genes; Goals; Hair Cells; Human; Image; Inbred CBA Mice; Ion Channel; Knockout Mice; Knowledge; Location; Longevity; Malignant Neoplasms; Mechanics; Mediating; Metabolism; Molecular; Mouse Strains; Mus; Neural Pathways; Neurodegenerative Disorders; Organ of Corti; Outer Hair Cells; Pathway interactions; Pattern; Pharmaceutical Preparations; Pilot Projects; Play; Population; Predisposition; Preparation; Presbycusis; Processed Genes; Property; Proteins; Radial; Reporting; Research; Role; Sensorineural Hearing Loss; Spectrin; Structure; Techniques; Testing; Therapeutic Intervention; Tissue-Specific Gene Expression; Up-Regulation; age related; aged; base; design; differential expression; experimental study; gene function; hearing impairment; in vivo; inhibitor/antagonist; insight; mechanical properties; mechanotransduction; middle ear; mouse model; novel; ototoxicity; protein structure function; prototype; rat Pres protein; response; sulfated glycoprotein 2; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; voltage clamp

Age-related hearing loss (ARHL), the most prevalent form of hearing loss in humans, is commonly caused by degenerative changes (or biological aging) and apoptosis of the cochlear inner and outer hair cells (IHCs, OHCs). Despite the fact that ARHL has been extensively studied using various mouse models, the causes of hair cell aging and apoptosis are still largely unknown. Our long-term goal is to examine the cellular and molecular mechanisms of biological aging of IHCs and OHCs. In the first part of the proposal we will attempt to answer two critical questions of how cochlear hair cells undergo aging, and why hair cell degeneration proceeds from the basal to the apical turn and from OHCs to IHCs. In the second part, we will focus on the molecular mechanisms of why OHCs are more susceptible to aging or other insults than IHCs by determining the roles of Clu, a gene that is differentially expressed in OHCs. A battery of electrophysiological, immunohistochemical, advanced imaging, and molecular biological techniques will be used to examine cellular changes in ultrastructure and mechanical and electrophysiological properties of IHCs and OHCs in the base and apex of the cochlea, respectively, in CBA/J strain mice during aging. Our hair cell-specific RNA-seq experiments using IHCs and OHCs obtained from younger and aging mice will enable us to reveal molecular mechanisms by identifying genes underlying age-related changes in IHCs and OHCs. We have three specific aims. Aim 1 is to examine the changes in mechanotransduction and mechanical and electrophysiological properties of hair cells during aging. Aim 2 is to examine the changes in gene expression underlying molecular mechanisms of aging of IHCs and OHCs. Aim 3 is to test the hypothesis that the elevated levels of Clu expression in OHCs relative to IHCs play a key role in the OHC’s selective susceptibility to aging. Completion of these aims is critical to understand the intrinsic cellular and molecular mechanisms of hair cell aging. The knowledge gained from this research is also essential for identifying targets for therapeutic intervention that aims to decelerate ARHL.

与年龄相关的听力损失（ARHL）是人类听力损失最普遍的形式，通常是由 耳蜗内部和外毛细胞的退化变化（或生物老化）和凋亡（IHC，OHC）。 尽管ARHL使用各种鼠标模型进行了广泛研究，但毛细胞的原因 衰老和细胞凋亡仍然在很大程度上未知。我们的长期目标是检查细胞和分子 IHC和OHC的生物衰老机制。在提案的第一部分中，我们将尝试回答 关于耳蜗毛细胞如何发生衰老的两个关键问题，以及为什么毛细胞变性从 顶端转弯以及从OHC到IHC的基本。在第二部分中，我们将专注于分子 为什么OHC比IHC更容易受到衰老或其他侮辱的机制。 Clu，在OHC中以不同表达的基因。一系列电生理，免疫组织化学， 高级成像和分子生物学技术将用于检查超微结构的细胞变化 以及耳蜗的基部和顶点的IHC和OHC的机械和电生理特性， 在衰老过程中，分别在CBA/J菌株小鼠中。使用IHCS和 从年轻小鼠和老化小鼠获得的OHC将使我们能够通过鉴定基因揭示分子机制 IHC和OHCS的基本与年龄相关的变化。我们有三个具体的目标。目标1是检查 衰老过程中毛细胞的机械转导以及机械和电生理特性的变化。 AIM 2是检查IHCS衰老和IHC衰老分子机制的基因表达的变化 OHCS。 AIM 3是检验以下假设：OHC相对于IHC的CLU表达升高播放 OHC对衰老的选择性敏感性中的关键作用。这些目标的完成至关重要 毛细胞老化的固有细胞和分子机制。这项研究所获得的知识也是 确定旨在减速ARHL的治疗干预靶标的目标。