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

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.

项目概要/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，巨噬细胞是人体中的主要免疫细胞。 耳蜗，在噪声性听力损失（NIHL）中。我们之前的研究表明，大脑中的巨噬细胞 具有不同的发育起源，并且它们的起源与其细胞身份的差异有关 功能取决于每种疾病的情况。目前，细胞特性和功能特性 噪声损伤后的巨噬细胞尚不清楚。将巨噬细胞命运图谱分析与 单细胞RNA测序，我们的初步数据显示，胚胎时期的耳蜗巨噬细胞 发育和健康成人有两个不同的起源。耳蜗的深入转录分析 稳定状态下单细胞分辨率的巨噬细胞证明了多种转录因子的存在 具有特定生物学功能的不同巨噬细胞簇。基于这些数据和我们之前的工作 脑巨噬细胞，我们假设不同来源的巨噬细胞参与 NIHL，具体取决于 动物的年龄和疾病的阶段（急性、恢复或康复）。它们独特的发育起源 导致转录多样性和对噪音损伤的不同反应。我们的研究结果将有助于 了解耳蜗巨噬细胞异质性及其与噪声后个体发育相关的功能 损害。定义耳蜗巨噬细胞群体的起源、差异基因表达和功能 将帮助我们加深对这些细胞在噪声损伤后不同阶段的作用的理解，并能够 我们设计基于炎症的新分子和细胞疗法。 具体目标 1：鉴定暴露的年轻成年和老年小鼠耳蜗巨噬细胞的细胞起源 到噪音损害。 具体目标 2：确定巨噬细胞通过单细胞 RNA 促进 NIHL 的机制 对耳蜗中存在的巨噬细胞群进行测序。