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.

摘要 耳蜗是内耳外周听觉系统的精细且结构复杂的部分， 对早期感染和炎症发育敏感。最近的研究表明， 常驻组织巨噬细胞（RTMs）分布在耳蜗的关键区域，并需要适当的 耳蜗发育我们的初步数据和已发表的数据确定耳蜗RTMs作为敏感的反应者 巨细胞病毒（CMV）感染，并与耳蜗损伤和感音神经性听力损失（SNHL）有关。而 胎儿来源的RTM已在耳蜗中被鉴定，但它们的确切来源和功能尚不清楚。RTM是 异质性，包括1）来源于卵黄囊造血的原始巨噬细胞和2）永久性巨噬细胞 来源于胎肝造血的巨噬细胞。我们将研究原始和 明确的RTMs在正常耳蜗发育，其空间分布在耳蜗内，并检查如何 这些相互作用响应CMV感染而出错，从而导致功能障碍。我们的调查提供了一个独特的 有机会了解组织环境如何影响表型，以及空间播种如何影响表型。 RTM影响正常组织发育和结构。我们的假设是巨细胞病毒感染 驱动异常的耳蜗RTM发育，从而损害耳蜗组织发育并引起SNHL。 我们将通过完成以下目标来研究这一假设： 目的1：确定耳蜗内特定RTM子集的起源、定位和贡献 目的2：了解特定RTM亚群在耳蜗组织发育和功能中的作用 目的3：确定CMV对胎源性RTM的建立和持续性的影响 这项拟议工作的目标是阐明新的水平的机制洞察力如何RTMs有助于 耳蜗组织和耳蜗免疫的正常功能，以及在疾病和病症的背景下，如何 RTMs介导CMV相关SNHL。这一建议将有助于阐明SNHL的病理机制， RTM和耳蜗组织。总的来说，拟议的工作将首次使我们深入了解 胎儿来源的常驻细胞和组织结构，并将提供RTMs作为一个潜在的新的见解 SNHL治疗的治疗靶点。