Mechanisms of Persistence and Recovery in Otitis Media

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往往是自限性的，但10- 20%的儿童患有持续性、复发性或慢性疾病。这种情况的长期形式会在语言习得和学习的关键时期造成听力损失，并有可能对中耳和内耳造成永久性损伤。目前的治疗方法，包括预防性或反复使用抗生素和手术干预，是有争议的，强调需要额外的治疗。持续性OM的原因，以及为什么有些儿童进展为持续性或复发性疾病，而其他儿童只经历一次或几次急性OM发作，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。这些包括有助于先天免疫的基因突变或多态性，控制感染的细胞过程如吞噬作用的缺陷，以及促进炎症恢复的细胞和组织系统的失调。在目前的支助期间获得的数据表明，这些机制也参与了持久性OM。在几个先天免疫基因突变的小鼠中，OM不能从OM中正常恢复。此外，OM持续性与巨噬细胞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的恢复期期间上调。在本申请中，Stephen Wasserman博士、艾伦瑞恩博士和Eyal Raz博士提出了一系列采用转基因小鼠的综合实验，以鉴定导致慢性OM的细胞和分子机制，并探索这种疾病的新疗法。本申请的目的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。目的2探讨不同表型的单核细胞源性细胞（包括巨噬细胞和树突状细胞）在OM中的作用。目的3将阐明中耳（ME）炎症恢复的调节机制，并确定促恢复因子是否可以改善急性和持续性ME疾病。这些研究将扩大我们对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，比其他任何儿童疾病都要多，估计花费50亿美元。此外，慢性和复发性中耳疾病导致在语言习得和学习的关键时期听力损失，具有语言延迟和学习困难以及中耳和内耳永久性损伤的风险。这项拟议中的研究将增加我们对中耳炎的理解，以及它为什么会变成慢性的，并将探索这种疾病的新疗法。

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.