Innate Immunity in Otitis Media Pathogenesis

描述(申请人提供)：继普通感冒之后，中耳炎(OM)或中耳炎是导致就诊的最常见疾病，也是导致儿童听力障碍的最常见原因。在过去的几十年里，在全世界范围内观察到引起OM的细菌的抗生素耐药性惊人的增加。然而，到目前为止，还没有开发出其他疗法来对抗这种疾病。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，必须了解控制先天性免疫分子表达的分子机制，这些分子构成了小管鼓室对入侵病原体的第一道防线，并确定这些机制是否可以用于预防或治疗OM。 在迄今测试的先天免疫分子中，β-防御素2是对OM病原体最有效的抗菌剂。然而，对NTHi调节该分子表达的分子机制知之甚少。我们的假设是，NTHi通过激活中耳上皮细胞中特定的信号通路上调β-防御素2。这与我们的长期目标一致，即研究具有良好特性的抗微生物天然免疫分子的表达，并阐明它们在OM发病机制中的作用。 为了实现我们的目标，我们将1)在体外和体内鉴定NTHi诱导的β-防御素2上调所需的上皮表面受体和受体相关的适配器组件，2)确定MKK3/6-P38A/β信号通路是否参与介导NTHi在体外和体内诱导的3-防御素2上调，以及3)证明NTHi和IL-1α可以通过不同的信号通路协同上调β-防御素2的表达。通过发现NTHi调节β-防御素2表达的信号通路，我们可能能够确定可以用于将该分子在管状鼓室中的表达上调至治疗水平的分子靶点。

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.