Mechanisms of Persistence and Recovery in Otitis Media

描述(申请人提供)：中耳炎(OM)是一个主要的健康问题，导致大量的医疗费用。超过90%的儿童经历过OM。虽然急性、不复杂的OM往往是自限性的，但10%-20%的儿童经历了持续性、复发性或慢性病。这种情况的长期形式会在语言学习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害。目前的治疗方法，包括预防性或重复使用抗生素和手术干预，都是有争议的，这突显了额外治疗的必要性。持续性OM的原因，以及为什么一些儿童进展为持续性或复发性疾病，而另一些儿童只经历一次或几次急性OM发作，目前尚不清楚。然而，最近发现了导致其他形式的慢性炎症性疾病的机制。这些问题包括抑制先天免疫的基因突变或多态，控制吞噬等感染的细胞过程中的缺陷，以及促进炎症恢复的细胞和组织系统调节失调。在本支助期间获得的数据表明，这些机制也参与了持久性OM。具有几个先天免疫基因突变的小鼠的OM不能从OM中正常恢复。此外，OM的持续性与巨噬细胞的行为和功能的变化有关。最后，在OM的恢复期，编码促恢复单核细胞表型以及促恢复因子及其受体的基因上调。在这项应用中，Stephen Wasserman博士、Allen Ryan博士和EYAL Raz博士提出了一系列综合实验，使用转基因小鼠来识别导致慢性OM的细胞和分子机制，并探索这种疾病的新疗法。这项应用的目的1将评估先天免疫结节样受体(NLR)信号通路在OM发病和恢复中的作用。目的2将探讨不同表型的单核细胞来源的细胞，包括巨噬细胞和树突状细胞在OM中的作用。目的3阐明炎症恢复在中耳(ME)中的调节机制，并确定促恢复因子是否能改善急性和持续性中耳疾病。总而言之，这些研究将扩大我们对OM恢复如何失败以及如何扭转这种失败的理解。 与公共卫生相关：中耳炎是幼儿最常见的疾病，比任何其他儿童疾病都要多去办公室就诊和做手术，估计花费50亿美元。此外，慢性和反复的中耳疾病会在语言习得和学习的关键时期导致听力损失，有语言延迟和学习困难的风险，并对中耳和内耳造成永久性损害。这项拟议的研究将增加我们对中耳炎及其变得慢性的原因的了解，并将探索治疗这种疾病的新形式。

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.