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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：
10459394
负责人：
Zhi-Zhou He
金额：
$ 37.66万
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 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459394
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 Persons 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 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，通常由以下因素引起