Mechanisms of Persistence and Recovery in Otitis Media

中耳炎的持续和恢复机制

• 批准号: 8020983
• 负责人: Stephen I Wasserman
• 金额: $ 31.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8020983
• 关键词: Accounting; Acute; Affect; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Attention; Behavior; Cell physiology; Cells; Child; Childhood; Chronic; Chronic Disease; Cicatrix; Conductive hearing loss; Data; Defect; Dendritic Cells; Disease; Event; Failure; Gene Expression Regulation; Generations; Genes; Genetic Polymorphism; Goals; Health; Health Expenditures; Immune; Immune response; Infection Control; Inflammation; Inflammatory; Labyrinth; Language Delays; Language Development; Lead; Learning; Lipids; Maintenance; Mediating; Molecular; Mus; Mutation; Natural Immunity; Nontypable Haemophilus influenza; Office Surgery; Office Visits; Operative Surgical Procedures; Otitis Media; Pathogenesis; Patients; Phagocytosis; Phase; Phenotype; Public Health; Receptor Signaling; Recovery; Recurrence; Recurrent disease; Research; Resolution; Risk; Role; Series; Signal Pathway; Signal Transduction; Signaling Molecule; System; Tissues; Work; cost; critical period; experience; hearing impairment; insight; macrophage; middle ear; middle ear disorder; monocyte; novel; programs; prophylactic; public health relevance; receptor; research study

DESCRIPTION (provided by applicant): Otitis media (OM) is a major health problem, resulting in substantial health care expenditures. More than 90% of children experience OM. While acute, uncomplicated OM tends to be self-limiting, 10- 20% of children experience persistent, recurrent or chronic disease. The long-lasting forms of this condition produce hearing loss during critical periods of language acquisition and learning, and carry a risk for permanent damage to the middle and inner ear. Current treatments, including prophylactic or repeated antibiotics and surgical interventions, are controversial, underscoring the need for additional therapies. The causes of persistent OM, and why some children progress to persistent or recurrent disease while others experience only one or a few episodes of acute OM, are not clear. However, mechanisms that contribute to other forms of chronic inflammatory diseases have recently been identified. These include mutations or polymorphisms in genes that subserve innate immunity, defects in cellular processes that control infection such as phagocytosis, and dysregulation of cellular and tissue systems that promote recovery from inflammation. Data obtained during the current period of support suggest the involvement of these mechanisms in persistent OM, as well. OM in mice with mutations in several innate immune genes fail to recover normally from OM. Moreover, OM persistence is correlated with changes in the behavior and function of macrophages. Finally, genes encoding pro-recovery monocyte phenotypes, as well as pro-recovery factors and their receptors, are up-regulated during the recovery phase of OM. In this application Drs. Stephen Wasserman, Allen Ryan and Eyal Raz propose a series of integrated experiments employing genetically modified mice to identify cellular and molecular mechanisms that lead to chronic OM, and to explore novel therapies for this condition. Aim 1 of this application will assess the contributions of innate immune NOD-like receptor (NLR) signaling pathways to OM pathogenesis and recovery. Aim 2 will investigate the role of different phenotypes of monocyte-derived cells, including macrophages and dendritic cells, in OM. Aim 3 will elucidate the mechanisms by which recovery from inflammation is regulated in the middle ear (ME), and determine whether pro-recovery factors can ameliorate acute and persistent ME disease. Together these studies will expand our understanding of how OM recovery can fail, and how this failure can be reversed. PUBLIC HEALTH RELEVANCE: Otitis media is the most common disease in young children, accounting for more office visits and surgery than any other childhood condition and costing an estimated five billion dollars. Moreover, chronic and recurrent middle ear disease leads to hearing loss during critical periods of language acquisition and learning, with a risk of language delay and learning difficulties and permanent damage to the middle and inner ear. The proposed research will increase our understanding of otitis media and why it becomes chronic, and will explore new forms of therapy for this condition.

描述（由申请人提供）：中耳炎（OM）是一个主要的健康问题，导致大量的医疗保健支出。超过 90% 的儿童经历过 OM。虽然急性、无并发症的 OM 往往具有自限性，但 10-20% 的儿童会经历持续性、复发性或慢性疾病。这种情况的长期持续形式会在语言习得和学习的关键时期产生听力损失，并有对中耳和内耳造成永久性损伤的风险。目前的治疗方法，包括预防性或重复使用抗生素以及手术干预，存在争议，这凸显了额外治疗的必要性。持续性 OM 的原因，以及为什么有些儿童会发展为持续性或复发性疾病，而其他儿童仅经历一次或几次急性 OM 发作，目前尚不清楚。然而，最近已经确定了导致其他形式的慢性炎症性疾病的机制。这些包括促进先天免疫的基因突变或多态性、控制感染的细胞过程的缺陷（例如吞噬作用）以及促进炎症恢复的细胞和组织系统的失调。当前支持期间获得的数据表明这些机制也参与了持久性 OM。一些先天免疫基因突变的小鼠的 OM 无法从 OM 中正常恢复。此外，OM 的持久性与巨噬细胞的行为和功能的变化相关。最后，编码促恢复单核细胞表型的基因以及促恢复因子及其受体在 OM 恢复阶段上调。在这个应用程序中，博士。 Stephen Wasserman、Allen Ryan 和 Eyal Raz 提出了一系列综合实验，利用转基因小鼠来鉴定导致慢性 OM 的细胞和分子机制，并探索针对这种疾病的新疗法。本申请的目标 1 将评估先天免疫 NOD 样受体 (NLR) 信号通路对 OM 发病机制和恢复的贡献。目标 2 将研究单核细胞衍生细胞（包括巨噬细胞和树突细胞）的不同表型在 OM 中的作用。目标 3 将阐明中耳 (ME) 炎症恢复的调节机制，并确定促恢复因素是否可以改善急性和持续性 ME 疾病。这些研究将共同​​加深我们对 OM 恢复如何失败以及如何逆转这种失败的理解。 公共卫生相关性：中耳炎是幼儿中最常见的疾病，其就诊和手术的次数比任何其他儿童疾病都多，估计花费 50 亿美元。此外，慢性和复发性中耳疾病会导致语言习得和学习关键时期的听力损失，并存在语言延迟和学习困难以及中耳和内耳永久性损伤的风险。拟议的研究将增加我们对中耳炎及其慢性化原因的了解，并将探索治疗这种疾病的新形式。