Innate Immunity in Otitis Media Pathogenesis

描述（由申请人提供）：继普通感冒之后，中耳炎（OM）或中耳炎症是导致儿童就诊的最常见疾病，也是最常见的听力障碍原因。在过去的几十年里，在世界范围内引起OM的细菌中观察到抗生素耐药性的惊人增长。到目前为止，还没有开发出其他治疗方法来对抗这种疾病。因此，迫切需要开发新的和创新的非抗生素方法来预防和管理OM。为此，有必要了解控制固有免疫分子表达的分子机制，这些分子构成了管状淋巴管抵御入侵病原体的第一道防线，并确定这些机制是否可以被利用来预防或治疗OM。

DESCRIPTION (provided by applicant): Following the common cold, otitis media (OM), or inflammation of the middle ear, is the most frequent illness resulting in visits to physicians and the most common cause of hearing impairment in children. During the past few decades, an alarming increase in antibiotic resistance has been observed worldwide in bacteria that cause OM. Yet to date, no other therapies have been developed to combat this disease. Thus, there is an urgent need to develop new and innovative non-antibiotic approaches to prevent and manage OM. To this end, it is imperative to understand the molecular mechanisms that control the expression of innate immune molecules that comprise the tubotympanum's first line of defense against invading pathogens and determine if these mechanisms can be exploited to prevent or treat OM. Of the innate immune molecules tested to date, beta-defensin 2 is the most effective antimicrobial against the OM pathogens. Little however, is known about the molecular mechanisms that regulate the expression of this molecule by NTHi. Our hypothesis is that NTHi up-regulates beta-defensin 2 via activation of specific signaling pathways in middle ear epithelial cells. This is in line with our long-term objective to study the expression of well-characterized antimicrobial innate immune molecules and elucidate their role in OM pathogenesis. Towards our objective, we will 1) Identify the epithelial surface receptors and the receptor-associated adaptor components required for NTHi-induced p-defensin 2 up-regulation in vitro and in vivo, 2) Determine if the the MKK3/6-p38a/beta signaling pathway is involved in mediating NTHi-induced (3-defensin 2 upregulation in vitro and in vivo, and 3) Demonstrate that NTHi and IL-1alpha can synergistically up-regulate the expression of beta-defensin 2, via distinct signaling pathways. By discovering the signaling pathways that regulate beta-defensin 2 expression by NTHi, we may be able to identify molecular targets that could be used to boost the expression of this molecule to therapeutic levels in the tubotympanum.