Investigating the origin and functional properties of immune cells in noise-induced hearing loss

研究噪声性听力损失中免疫细胞的起源和功能特性

• 批准号: 10731667
• 负责人: Bahareh Ajami
• 金额: $ 20.62万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-12 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731667
• 关键词: Acute; Adult; Age; Anatomy; Animals; Anti-Inflammatory Agents; Biological; Biological Process; Brain; Cell Therapy; Cells; Characteristics; Cochlea; Collaborations; Data; Development; Disease; Disease Progression; Effectiveness; Embryo; Embryonic Development; Exposure to; Future; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Growth; Hearing; Heterogeneity; Homeostasis; Human; Immune; Inflammation; Inflammatory; Injury; Intervention; Knowledge; Label; Labyrinth; Letters; Location; Macrophage; Maps; Modeling; Molecular; Molecular Profiling; Molecular Target; Morphology; Mus; Noise; Noise-Induced Hearing Loss; Parabiosis; Pathogenicity; Pathology; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Population; Prevalence; Property; Recovery; Regenerative pathway; Resolution; Role; Steroids; Temporary Threshold Shift; Therapeutic Intervention; Tissue-Specific Gene Expression; Transgenic Organisms; Visit; Work; World Health Organization; aged; body system; cellular targeting; design; drug discovery; effective therapy; experimental study; gene function; hearing impairment; hearing loss risk; insight; monocyte; noise exposure; normal hearing; progenitor; regenerative cell; response; side effect; single-cell RNA sequencing; therapeutic target; transcriptomics; young adult; Acute; Adult; Age; Anatomy; Animals; Anti-Inflammatory Agents; Biological; Biological Process; Brain; Cell Therapy; Cells; Characteristics; Cochlea; Collaborations; Data; Development; Disease; Disease Progression; Effectiveness; Embryo; Embryonic Development; Exposure to; Future; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Growth; Hearing; Heterogeneity; Homeostasis; Human; Immune; Inflammation; Inflammatory; Injury; Intervention; Knowledge; Label; Labyrinth; Letters; Location; Macrophage; Maps; Modeling; Molecular; Molecular Profiling; Molecular Target; Morphology; Mus; Noise; Noise-Induced Hearing Loss; Parabiosis; Pathogenicity; Pathology; Pathway interactions; Pharmaceutical Preparations; Phase; Play; Population; Prevalence; Property; Recovery; Regenerative pathway; Resolution; Role; Steroids; Temporary Threshold Shift; Therapeutic Intervention; Tissue-Specific Gene Expression; Transgenic Organisms; Visit; Work; World Health Organization; aged; body system; cellular targeting; design; drug discovery; effective therapy; experimental study; gene function; hearing impairment; hearing loss risk; insight; monocyte; noise exposure; normal hearing; progenitor; regenerative cell; response; side effect; single-cell RNA sequencing; therapeutic target; transcriptomics; young adult

PROJECT SUMMARY/ABSTRACT In this proposed work, we seek to understand the cellular identity of macrophages, the main immune cells in the cochlea, in noise-induced hearing loss (NIHL). Our previous studies have shown that macrophages in the brain have different developmental origins and their origin is associated with differences in their cellular identity and functions depending on each disease condition. At present, the cellular identities and functional properties of macrophages after noise damage are not well understood. Combining macrophage fate-mapping analysis with single-cell RNA sequencing, our preliminary data revealed that cochlea macrophages during embryonic development and in healthy adult are from two distinct origins. In-depth transcriptional analysis of cochlea macrophages at single-cell resolution in steady state demonstrated the presence of several transcriptionally distinct clusters of macrophages with specific biological functions. Based on this data and our previous work on brain macrophages, we hypothesize that macrophages from different origins are involved in NIHL depending on the age of the animal and stage of the disease (acute, recovery or recovered). Their distinct developmental origin results in transcriptional diversity and differential responses to noise damage. Our findings will contribute to the understanding of cochlea macrophage heterogeneity and functions in relation to their ontogeny after noise damage. Defining the origins and differential gene expression and functions of cochlea macrophage populations will help us to refine our understanding of the role of these cells in different stage after noise damage and enable us to design new molecular and cellular therapies based on targeting inflammation. Specific Aim 1: Identifying the cellular origin of cochlea macrophages in young adult and aged mice exposed to noise damage. Specific Aim 2: Identifying mechanisms by which macrophages contribute to NIHL through single-cell RNA sequencing of macrophage populations present in cochlea.

项目摘要/摘要 在这项拟议的工作中，我们试图了解巨噬细胞的细胞身份，即巨噬细胞的主要免疫细胞 耳蜗，噪声引起的听力损失（NIHL）。我们以前的研究表明大脑中的巨噬细胞 具有不同的发育起源，其起源与其细胞身份的差异有关 功能取决于每种疾病状况。目前，细胞身份和功能特性 噪声损伤后的巨噬细胞尚不清楚。将巨噬细胞命运分析与 单细胞RNA测序，我们的初步数据表明，胚胎中的耳蜗巨噬细胞 发展和健康的成年人来自两个不同的起源。耳蜗的深入转录分析 稳态下单细胞分辨率的巨噬细胞证明存在几种转录 具有特定生物学功能的巨噬细胞的不同簇。根据这些数据以及我们以前的工作 大脑巨噬细胞，我们假设来自不同起源的巨噬细胞与NIHL有关 动物的年龄和疾病的阶段（急性，恢复或恢复）。他们独特的发展起源 导致转录多样性和对噪声损害的差异反应。我们的发现将有助于 了解耳蜗的异质性和功能相对于其本体发育的功能 损害。定义耳蜗种群的起源和差异基因表达和功能 将帮助我们完善对这些细胞在噪声破坏后不同阶段的作用的理解，并启用 我们根据靶向炎症设计新的分子和细胞疗法。 特定目标1：识别年轻小鼠和老年小鼠的耳蜗巨噬细胞的细胞来源 噪声损坏。 特定目标2：识别巨噬细胞通过单细胞RNA促进NIHL的机制 耳蜗中存在的巨噬细胞的测序。