The role of macrophages in chronic suppurative otitis media associated sensory hearing loss

巨噬细胞在慢性化脓性中耳炎相关感觉性听力损失中的作用

• 批准号: 10754782
• 负责人: Peter Luke Santa Maria
• 金额: $ 9.12万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754782
• 关键词: Animal Model; Bacteria; Bacterial Infections; Cd68; Cell Death; Child; Chronic; Cochlea; Communities; Development; Disease; Dose; Ear; Fluoroquinolones; Functional disorder; Future; Hair Cells; Human; Immune; Infection; Inflammasome; Invaded; Investigation; Knockout Mice; Labyrinth; Macrophage; Medical; Microbial Biofilms; Modeling; Mouse Strains; Mus; Nature; Otitis Media; Perilymph; Persons; Phenotype; Population; Process; Pseudomonas aeruginosa; Reactive Oxygen Species; Reporter Genes; Role; Sampling; Sensorineural Hearing Loss; Suppurative Otitis Media; Therapeutic Intervention; Time; Topical Antibiotic; Toxin; Transgenic Organisms; Tympanic membrane; United States National Institutes of Health; Waxes; World Health; acute infection; effective therapy; hearing impairment; human disease; middle ear; migration; mouse model; neglected tropical diseases; novel; novel strategies; permanent hearing loss; prevent; Animal Model; Bacteria; Bacterial Infections; Cd68; Cell Death; Child; Chronic; Cochlea; Communities; Development; Disease; Dose; Ear; Fluoroquinolones; Functional disorder; Future; Hair Cells; Human; Immune; Infection; Inflammasome; Invaded; Investigation; Knockout Mice; Labyrinth; Macrophage; Medical; Microbial Biofilms; Modeling; Mouse Strains; Mus; Nature; Otitis Media; Perilymph; Persons; Phenotype; Population; Process; Pseudomonas aeruginosa; Reactive Oxygen Species; Reporter Genes; Role; Sampling; Sensorineural Hearing Loss; Suppurative Otitis Media; Therapeutic Intervention; Time; Topical Antibiotic; Toxin; Transgenic Organisms; Tympanic membrane; United States National Institutes of Health; Waxes; World Health; acute infection; effective therapy; hearing impairment; human disease; middle ear; migration; mouse model; neglected tropical diseases; novel; novel strategies; permanent hearing loss; prevent

Project Summary / Abstract We request NIH support to investigate how sensory hearing loss (SHL) is caused by chronic suppurative otitis media (CSOM) or severe chronic middle ear infections. CSOM, a neglected tropical disease that afflicts 330 million people worldwide, is the most common cause of permanent hearing loss among children in the developing world. It is characterized by a chronically discharging infected middle ear, and there is currently no effective medical therapy or cure. The bacterium, Pseudomonas aeruginosa (PA), is the leading culprit. PA colonizes the middle ear via a hole in the tympanic membrane and establishes itself into a biofilm community, complicating attempts to treat and fully eradicate infection. Over the course of the disease, the infection waxes and wanes as the population of bacteria within the biofilm responds, in part, to immune attack or topical antibiotics. This waxing and waning of bacterial infection leads to permanent sensory hearing loss via an unknown mechanism. Our lab has recently created and validated a novel PA CSOM animal model that mimics the human condition. Specifically, we create the infection by inoculating PA in the right state (phenotype) and dose, which results in an infection that persists beyond six months, waxes and wanes upon topical fluoroquinolone therapy, and leads to hair cell death, over time, like in the human disease. Previous investigations by others relied on acute infection models based on non-PA bacteria. In contrast, our unique model of PA CSOM now allows us to observe development of the infection in the inner ear and identify agents and/or processes that may be causing the resulting sensory hearing loss. Our studies would help determine whether permanent hearing loss is preventable in CSOM and, if so, guide strategies for therapeutic intervention. Our Aims encompass: (1) determining the timing and nature of structural changes occurring within the cochlea and assessing the macrophage distribution as these changes occur, (2) investigating potential direct hair cell (HC) toxins and macrophage inducers through CSOM perilymph sampling, and (3) evaluating the contributions of resident and migrating macrophages towards hair cell loss in CSOM by combining our CSOM mouse model with the CD68-GFP transgenic reporter mouse and, separately, with a triple knockout mouse strain with macrophages unable to produce reactive oxygen species (ROS) while also evaluating whether NLRP3 inflammasome function is necessary for HC loss in the cochlea. Altogether these aims are a completely new approach to sensory hearing loss caused by CSOM. If successful, these studies will support future investigations into the mechanisms in the pathophysiology of CSOM and lead to novel treatments for PA and potential strategies to prevent sensory hearing loss in CSOM.

项目摘要 /摘要 我们要求NIH支持，以调查感觉听力损失（SHL）是如何由慢性化脓性中耳炎引起的 培养基（CSOM）或严重的慢性中耳感染。 CSOM，一种受忽视的热带疾病330 全世界有百万人民，是儿童永久性听力损失的最常见原因 发展中国家。它的特征是长期释放的中耳感染，目前没有 有效的医疗疗法或治愈。细菌铜绿假单胞菌（PA）是领先的罪魁祸首。 PA 通过鼓膜膜中的一个孔殖民中耳，并将自己建立成生物膜群落， 使治疗和完全消除感染的尝试复杂化。在疾病过程中，感染蜡 随着生物膜内细菌的种群的减弱，部分反应了免疫攻击或局部 抗生素。细菌感染的这种上蜡和减弱导致通过 未知机制。我们的实验室最近创建并验证了一种新颖的PA CSOM动物模型 人类状况。具体而言，我们通过以正确的状态接种PA（表型）和 剂量会导致感染持续超过六个月，蜡和局部衰竭 像人类疾病一样，氟喹诺酮治疗，并导致毛细胞死亡。以前的 其他人的研究依赖于基于非PA细菌的急性感染模型。相反，我们的独特 现在，PA CSOM的模型使我们能够观察内耳中感染的发展并识别药物 和/或可能导致感觉听力损失的过程。我们的研究将有助于确定 CSOM是否可以预防永久性听力损失，如果是的，则指导治疗干预的策略。 我们的目标包括：（1）确定耳蜗内发生的结构变化的时间和性质 并随着这些变化的发生评估巨噬细胞分布，（2）研究潜在的直接毛细胞 （HC）毒素和巨噬细胞通过CSOM PerilyMph采样，（3）评估贡献 通过组合我们的CSOM鼠标模型，居民和将巨噬细胞迁移到CSOM中的毛细胞损失 使用CD68-GFP转基因报告基因小鼠，并分别使用三重基因敲除小鼠应变 巨噬细胞无法产生活性氧（ROS），同时还评估NLRP3是否是否 炎性体功能对于耳蜗中的HC损失是必需的。 这些目标总的来说是CSOM引起的感觉听力损失的全新方法。如果成功， 这些研究将支持对CSOM病理生理机制的未来研究，并领导 对PA的新治疗方法和潜在的策略，以防止CSOM的感觉听力损失。