Mechanisms of Biological Aging of Cochlear Hair Cells

耳蜗毛细胞的生物衰老机制

• 批准号: 9979632
• 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/9979632
• 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.

年龄相关性听力损失(ARHL)是人类最常见的听力损失形式，通常由 耳蜗内、外毛细胞的退行性变化(或生物老化)和细胞凋亡。 尽管ARHL已经在各种小鼠模型上得到了广泛的研究，但毛细胞的原因 衰老和细胞凋亡在很大程度上仍是未知的。我们的长期目标是研究细胞和分子 间质细胞和毛细胞的生物老化机制。在提案的第一部分，我们将尝试回答 两个关键问题：耳蜗毛细胞是如何衰老的，以及为什么毛细胞退化是由 从基底部到顶端转折，从毛细胞到间质细胞。在第二部分中，我们将重点介绍分子 通过确定OHC的角色来解释为什么OHC比IHC更容易受到老化或其他侮辱的影响 Clu，一种在OHC中差异表达的基因。一组电生理，免疫组织化学， 先进的成像和分子生物学技术将被用来检查细胞超微结构的变化 以及耳蜗基底部和顶端的间质细胞和毛细胞的机械和电生理特性， 分别在CBA/J系小鼠衰老过程中进行检测。我们的毛细胞特异性RNA-SEQ实验使用IHC和 从年轻和衰老小鼠身上获得的OHC将使我们能够通过识别基因来揭示分子机制 IHC和OHC潜在的与年龄相关的变化。我们有三个具体目标。目标1是检查 衰老过程中毛细胞的机械转导及机械和电生理特性的变化。 目的2研究IHC衰老分子机制中基因表达的变化。 毛囊虫。目标3是检验假设，即相对于间质细胞而言，毛细胞中Clu表达水平的升高起到了 在OHC对衰老的选择性敏感性中起关键作用。完成这些目标对于理解 毛细胞衰老的内在细胞和分子机制。从这项研究中获得的知识也是 对于确定旨在减慢急性淋巴细胞性白血病的治疗干预的目标至关重要。