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

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，巨噬细胞是人体内的主要免疫细胞 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 有不同的发育起源，它们的起源与它们的细胞身份和 根据每种疾病的情况发挥作用。目前，细胞的同一性和功能特性 噪声损伤后的巨噬细胞还不是很清楚。将巨噬细胞命运图分析与 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 发育和健康的成年人来自两个不同的来源。深入分析耳蜗骨的转录 巨噬细胞在稳定状态下的单细胞分辨率显示存在多个转录水平的 具有特定生物功能的不同的巨噬细胞群。基于这些数据和我们之前在 脑巨噬细胞，我们假设来自不同来源的巨噬细胞参与NIHL取决于 动物的年龄和疾病的阶段(急性、恢复期或恢复期)。它们独特的发育起源 导致转录多样性和对噪声损伤的差异反应。我们的发现将有助于 噪声后耳蜗巨噬细胞异质性及其功能与个体发育的关系 损坏。确定耳蜗巨噬细胞群体的起源、差异基因表达和功能 将有助于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，并使 美国将设计基于炎症靶向的新分子和细胞疗法。 具体目标1：确定幼年和老年小鼠耳蜗巨噬细胞的细胞来源 对噪音的损害。 具体目标2：确定巨噬细胞通过单细胞RNA促进NIHL的机制 对存在于耳蜗处的巨噬细胞群体进行测序。

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.