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: 10675667
• 负责人: Hainan Lang
• 金额: $ 40.86万
• 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/10675667
• 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; Immune response; Inflammatory; Innate Immune Response; Innate Immune System; Ion Transport; Labyrinth; Lateral; Link; Lipids; Macrophage; 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; Role; Signal Transduction; Signaling Molecule; Stria Vascularis; Study Subject; Temporal bone structure; Testing; Tissue-Specific Gene Expression; Tissues; age related; age related neurodegeneration; aged; cell type; complement system; experimental study; functional decline; hearing impairment; human subject; human tissue; in vivo; mRNA Expression; mouse model; multidisciplinary; neural; new therapeutic target; prevent; protein expression; response; sphingosine 1-phosphate; superresolution imaging; transcriptome sequencing; 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; Immune response; Inflammatory; Innate Immune Response; Innate Immune System; Ion Transport; Labyrinth; Lateral; Link; Lipids; Macrophage; 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; Role; Signal Transduction; Signaling Molecule; Stria Vascularis; Study Subject; Temporal bone structure; Testing; Tissue-Specific Gene Expression; Tissues; age related; age related neurodegeneration; aged; cell type; complement system; experimental study; functional decline; hearing impairment; human subject; human tissue; in vivo; mRNA Expression; mouse model; multidisciplinary; neural; new therapeutic target; prevent; protein expression; response; sphingosine 1-phosphate; superresolution imaging; 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（长期）是一种常见的神经退行性疾病，可以是 与人工耳蜗侧壁的几种专用细胞类型的损失和/或功能障碍有关（代谢 长老会）和听觉神经（神经长老会）。临床研究中心的项目2旨在 使用使用人类代谢和神经元的临界细胞和分子机制使用使用 小鼠模型和验尸后人类临时骨骼来自年轻和年龄较大的捐助者。失调的 小胶质细胞/巨噬细胞和完成级联，这是先天免疫的两个基本元素 系统已被证明在几种与年龄有关的神经退行性疾病中起着至关重要的作用。我们的 初步研究表明，人工耳蜗可能会经历结构和分子 随着年龄的增长的变化，表明功能变化，这些变化与 老年小鼠人工耳蜗侧壁微脉管系统的病理变化。鞘氨醇1-磷酸盐 （S1P），一种脂质信号分子，调节巨噬细胞活性。基因表达的初步研究 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还原之间有联系 在S1P生物利用度中，人工耳蜗侧壁的年龄增加和巨噬细胞功能障碍。此外， 小鼠听觉神经中的差异基因表达分析已确定了随着增加的重大变化 先天免疫响应和完成级联途径的年龄。对其他的最新研究 神经退行性疾病表明，完成失调会导致脱髓鞘和神经元 退化。基于这些观察结果，我们的总体假设是年龄依赖性失调 人工耳蜗先天免疫系统促成衰老中专业细胞的变性 墙壁和听觉神经，导致听觉功能下降与代谢和神经元一致 长老会。项目2将确定S1P介导的巨噬细胞功能障碍与 衰老小鼠的侧壁中脊柱微脉管变性（AIM 2.1）； 2）阐明链接 在与年龄相关的完整系统失调之间，发展和功能下降 听觉神经纤维，特别是赞助率低的纤维（AIM 2.2）。侧壁的动物模型 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研究的人类受试者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类中进行检查 临时骨骼，通过人类受试者核心访问（核心B）。比较的能力 动物模型，人类临时骨骼和人类受试者的结果提供了无与伦比的机会 解决有关人工耳蜗功能障碍和完成的特定作用的问题 与人的长老会有关的血管和髓神经胶质病理生理学调节。