Project 2: Mechanistic studies of age-related hearing loss using animal models and human tissue

项目2：利用动物模型和人体组织研究年龄相关性听力损失的机制

• 批准号: 10470232
• 负责人: Hainan Lang
• 金额: $ 41.28万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470232
• 关键词: Acoustic Nerve; Action Potentials; Address; Age; Aging; Animal Model; Auditory; Autopsy; Biological Assay; Biological Availability; Blood Vessels; CBA/CaJ Mouse; Carrier Proteins; Cells; Cellular biology; Characteristics; Clinical Research; Cochlea; Comparative Study; Complement; Demyelinations; Elements; Fiber; Functional disorder; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Human; Image; Immune response; Inflammatory; Innate Immune Response; Innate Immune System; Ion Transport; Labyrinth; Lateral; Lead; Link; Lipids; Measurement; Measures; Mediating; Metabolic; Microglia; Modeling; Molecular; Morphology; Mus; Mutation; Myelin; Nerve Degeneration; Nerve Fibers; Neurodegenerative Disorders; Neuroglia; Neurons; Pathologic; Pathway interactions; Pattern; Physiological; Play; Presbycusis; Recovery of Function; Regulation; Resolution; Role; Signal Transduction; Signaling Molecule; Stria Vascularis; Study Subject; Temporal bone structure; Testing; Tissue-Specific Gene Expression; Tissues; age related; age related neurodegeneration; aged; base; cell type; complement system; experimental study; functional decline; hearing impairment; human subject; human tissue; in vivo; mRNA Expression; macrophage; mouse model; multidisciplinary; new therapeutic target; prevent; protein expression; relating to nervous system; response; sphingosine 1-phosphate; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT – PROJECT 2 Age-related hearing loss (presbyacusis) is a common neurodegenerative disorder that can be associated with loss and/or dysfunction of several specialized cell types in the cochlear lateral wall (metabolic presbyacusis) and the auditory nerve (neural presbyacusis). Project 2 of the Clinical Research Center aims to identify critical cellular and molecular mechanisms underlying human metabolic and neural presbyacusis using mouse models and post-mortem human temporal bones from younger and older donors. Dysregulation of microglia/macrophages and the complement cascade, two fundamental elements of the innate immune system, have been shown to play vital roles in several age-related neurodegenerative disorders. Our preliminary studies have revealed that cochlear macrophages may undergo structural and molecular alterations with increasing age, indicative of functional changes, and that these alterations are associated with pathological changes in the cochlear lateral wall microvasculature of aged mice. Sphingosine-1-phosphate (S1P), a lipid signaling molecule, regulates macrophage activity. Preliminary studies of gene expression patterns and age-related macrophage dysfunction in mouse cochlear tissue suggest a link between a reduction in S1P bioavailability with increasing age and macrophage dysfunction in the cochlear lateral wall. In addition, differential gene expression analysis in the mouse auditory nerve has identified major changes with increasing age in the innate immune response and complement cascade pathways. Recent studies of other neurodegenerative disorders have shown that complement dysregulation can lead to demyelination and neural degeneration. Based on these observations, our overarching hypothesis is that age-dependent dysregulation of the cochlear innate immune system contributes to the degeneration of specialized cells in the aging lateral wall and auditory nerve, leading to declines in auditory function consistent with metabolic and neural presbyacusis. Project 2 will 1) determine the relationship between S1P-mediated macrophage dysfunction and strial microvasculature degeneration in the lateral wall of aged mice (Aim 2.1); and 2) elucidate the links between age-related dysregulation of the complement system with degeneration and functional declines in auditory nerve fibers, in particular fibers with low spontaneous rates (Aim 2.2). Animal models of lateral wall and auditory nerve degeneration characterized in Project 2 will also be used to validate genetic and pathophysiology results obtained from human subjects studied in Projects 1, 3, and 4. Comparative studies of the expression patterns of these key immune response regulatory molecules will also be examined in human temporal bones, which are accessed through the Human Subjects Core (Core B). The ability to compare results from animal models, human temporal bones, and human subjects provides an unparalleled opportunity to address questions regarding the specific role of the cochlear macrophage dysfunction and complement regulation in vascular and myelinating glial pathophysiology associated with human presbyacusis.

项目摘要/摘要 – 项目 2 与年龄相关的听力损失（老年性听力损失）是一种常见的神经退行性疾病，可以通过 与耳蜗侧壁中几种特殊细胞类型的损失和/或功能障碍有关（代谢 临床研究中心项目2旨在研究老年性耳聋）和听觉神经（神经性老年性耳聋）。 使用以下方法识别人类代谢和神经老年性耳聋背后的关键细胞和分子机制 来自年轻和年长捐赠者的小鼠模型和死后人类颞骨。 小胶质细胞/巨噬细胞和补体级联，先天免疫的两个基本要素 系统已被证明在几种与年龄相关的神经退行性疾病中发挥着重要作用。 初步研究表明，耳蜗巨噬细胞可能经历结构和分子 随着年龄的增长而发生的变化，表明功能的变化，并且这些变化与 老年小鼠耳蜗侧壁微血管的病理变化。1-磷酸鞘氨醇。 (S1P)，一种脂质信号分子，调节巨噬细胞活性的初步研究。 小鼠耳蜗组织中的模式和与年龄相关的巨噬细胞功能障碍表明减少之间存在联系 S1P 生物利用度随着年龄的增加和耳蜗侧壁巨噬细胞功能障碍而增加。 小鼠听觉神经的差异基因表达分析发现随着增加的增加发生了重大变化 年龄在先天免疫反应和补体级联途径中的最新研究。 神经退行性疾病已表明补体失调可导致脱髓鞘和神经退行性疾病 基于这些观察，我们的总体假设是年龄依赖性失调。 耳蜗先天免疫系统的退化导致衰老侧耳蜗特化细胞的退化 壁和听觉神经，导致听觉功能下降，与代谢和神经一致 项目 2 将 1) 确定 S1P 介导的巨噬细胞功能障碍与老年性耳聋之间的关系。 老年小鼠侧壁的心房微血管变性（目标 2.1）；以及 2）阐明其中的联系 与年龄相关的补体系统失调与退化和功能下降之间的关系 听觉神经纤维，特别是自发率低的纤维（目标 2.2）。 项目 2 中表征的听觉神经变性也将用于验证遗传和 从项目 1、3 和 4 中研究的人类受试者中获得的病理生理学结果。 这些关键免疫反应调节分子的表达模式也将在人体中进行检查 颞骨，通过人类受试者核心（核心 B）进行比较的能力。 动物模型、人类颞骨和人类受试者的结果提供了无与伦比的机会 解决有关耳蜗巨噬细胞功能障碍和补体的具体作用的问题 与人类老年痴呆相关的血管和髓鞘神经胶质病理生理学的调节。