The role of resident tissue macrophages in cytomegalovirus-associated sensorineural hearing loss

常驻组织巨噬细胞在巨细胞病毒相关感音神经性听力损失中的作用

• 批准号: 10827172
• 负责人: Kelly Otsuka
• 金额: $ 4.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10827172
• 关键词: Acute; Affect; Architecture; Area; Auditory system; Bone Marrow; Cell physiology; Cells; Cochlea; Complex; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Disease; Environment; Fetal Liver; Functional disorder; Goals; Grant; Hematopoiesis; Hematopoietic; Homeostasis; Human; Immune; Immunity; Impairment; Infection; Inflammation; Investigation; Label; Labyrinth; Lead; Life; Link; Location; Longevity; Macrophage; Maintenance; Maps; Mediating; Mus; Normal tissue morphology; Pathogenesis; Pathologic; Pattern; Peripheral; Phenotype; Population; Publishing; Role; Sensorineural Hearing Loss; Spatial Distribution; Symptoms; System; Testing; Time; Tissues; Toxoplasmosis; Viral; Work; Yolk Sac; cochlear development; congenital cytomegalovirus; congenital infection; defined contribution; effective therapy; fetal; hearing loss treatment; improved; insight; mouse model; new therapeutic target; non-genetic; novel; postnatal; prenatal; prevent; response; spatiotemporal; tissue repair

ABSTRACT The cochlea is a delicate and structurally complex part of the inner ear peripheral auditory system that is developmentally sensitive to early life infection and inflammation. Recent studies have shown fetal-derived resident tissue macrophages (RTMs) are distributed across key areas of the cochlea, and are required for proper cochlea development. Our preliminary data and published data identify cochlea RTMs as sensitive responders to cytomegalovirus (CMV) and are implicated in cochlear damage and sensorineural hearing loss (SNHL). While fetal-derived RTMs have been identified in cochlea, their precise origin and function is unknown. RTMs are heterogeneous and include 1) primitive macrophages derived from yolk sac hematopoiesis and 2) definitive macrophages derived from fetal liver hematopoiesis. We will investigate relative contribution of primitive and definitive RTMs in normal cochlea development, their spatial distribution within the cochlea, and examine how these interactions go awry in response to CMV infection to drive dysfunction. Our investigation offers a unique opportunity to understand both how tissue environment can influence phenotype and how spatial seeding of RTMs influences normal tissue development and architecture. Our working hypothesis is that CMV infection drives abnormal cochlea RTM development, thereby impairing cochlea tissue development and causing SNHL. We will investigate this hypothesis by completing our following aims: Aim 1: Determine the origin, localization, and contribution of specific RTM subsets within the cochlea Aim 2: Understand the role of specific RTM subsets in cochlear tissue development and function Aim 3: Determine the impact of CMV on the establishment and persistence of fetal-derived RTMs The objective of this proposed work is to elucidate new level of mechanistic insight into how RTMs contribute to normal function of cochlea tissue and cochlear immunity, and within the context of disease and disorders, how RTMs mediate CMV-associated SNHL. This proposal will shed light on pathological mechanisms of SNHL on RTM and cochlea tissue. Collectively the proposed work will, for the first time, give us insight into the link between fetal-derived resident cells and tissue architecture, and will provide insight for RTMs as a potential novel therapeutic target for SNHL treatment.

抽象的 耳蜗是内耳外围听觉系统的微妙且结构上复杂的部分 发育对早期生命感染和炎症敏感。最近的研究表明胎儿衍生 居民组织巨噬细胞（RTMS）分布在耳蜗的关键区域，需要正确 耳蜗发展。我们的初步数据和已发布的数据将Cochlea RTMS识别为敏感响应者 到巨细胞病毒（CMV），与人工耳蜗损伤和感觉性听力损失（SNHL）有关。尽管 胎儿衍生的RTM已在耳蜗中鉴定出来，其精确的起源和功能尚不清楚。 RTMS是 异质性，包括1）源自蛋黄囊造血的原始巨噬细胞和2）确定性 源自胎儿肝造血的巨噬细胞。我们将研究原始和 正常耳蜗发育中的确定性RTM，其在耳蜗内的空间分布，并检查如何 这些相互作用因响应CMV感染而出差以驱动功能障碍。我们的调查提供了独特的 了解组织环境如何影响表型以及如何进行空间播种的机会 RTM会影响正常的组织发育和结构。我们的工作假设是CMV感染 驱动异常耳蜗RTM发育，从而损害耳蜗组织的发育并引起SNHL。 我们将通过完成以下目标来调查这一假设： 目标1：确定耳蜗内特定RTM子集的起源，本地化和贡献 目标2：了解特定RTM子集在耳蜗组织发育和功能中的作用 目标3：确定CMV对胎儿衍生RTM的建立和持久性的影响 这项拟议工作的目的是阐明对RTMS如何做出贡献的新机械洞察力 耳蜗组织和耳蜗免疫的正常功能，在疾病和疾病的背景下，如何 RTMS介导与CMV相关的SNHL。该建议将阐明SNHL的病理机制 RTM和耳蜗组织。拟议的工作总共将首次洞悉 胎儿衍生的居民细胞和组织结构，将为RTMs提供潜在的新颖的见解 SNHL治疗的治疗靶标。