Mechanisms of Biological Aging of Cochlear Hair Cells

耳蜗毛细胞的生物衰老机制

基本信息

批准号：
10174906
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
项目类别：
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/10174906
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

项目摘要

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，通常由以下原因引起耳蜗内毛细胞和外毛细胞（IHC、OHC）的退行性变化（或生物衰老）和凋亡。尽管 ARHL 已使用各种小鼠模型进行了广泛研究，但毛细胞的原因衰老和细胞凋亡在很大程度上仍然是未知的，我们的长期目标是检查细胞和分子。在提案的第一部分，我们将尝试回答 IHC 和 OHC 的生物衰老机制。两个关键问题是耳蜗毛细胞如何经历衰老，以及毛细胞退化为何发生基底到顶端的转变以及从 OHC 到 IHC 在第二部分中，我们将重点关注分子。通过确定 OHC 比 IHC 更容易受到衰老或其他损伤的机制 Clu，一种在 OHC 中差异表达的基因，包括电生理学、免疫组织化学、先进的成像和分子生物学技术将用于检查细胞超微结构的变化以及耳蜗基部和顶端 IHC 和 OHC 的机械和电生理特性，我们分别使用 IHC 和 CBA/J 品系小鼠在衰老过程中进行毛细胞特异性 RNA 测序实验。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 中与年龄相关的潜在变化我们有三个具体目标。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。目标 2 是检查 IHC 衰老分子机制下基因表达的变化和 OHC 的目标 3 是检验 OHC 中 Clu 表达水平相对于 IHC 的升高发挥作用的假设。 OHC 选择性易感性衰老的关键作用完成这些目标对于理解这一点至关重要。从这项研究中获得的知识还包括毛细胞衰老的内在细胞和分子机制。对于确定旨在减缓 ARHL 的治疗干预目标至关重要。