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%的儿童会出现持续性、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方法。持续性OM的病因，以及为什么有些儿童发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。这些包括先天免疫的基因突变或多态性，控制感染的细胞过程缺陷，如吞噬作用，以及促进炎症恢复的细胞和组织系统失调。在当前支助期间获得的数据表明，这些机制也参与了持续的OM。在一些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的持续性与巨噬细胞行为和功能的改变有关。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提出了一系列采用转基因小鼠的综合实验，以确定导致慢性OM的细胞和分子机制，并探索这种疾病的新疗法。本应用的目的1将评估先天免疫nod样受体（NLR）信号通路在OM发病和恢复中的作用。目的2将研究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将阐明炎症恢复在中耳（ME）调节的机制，并确定促恢复因子是否可以改善急性和持续性ME疾病。总之，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。

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.