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）或中耳炎症是导致就诊的最常见疾病，也是儿童听力障碍的最常见原因。在过去的几十年里，在全球范围内观察到引起OM的细菌中抗生素耐药性的惊人增加。迄今为止，尚未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，必须了解控制先天免疫分子表达的分子机制，这些分子构成了咽鼓管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。 在迄今为止测试的先天免疫分子中，β-防御素2是针对OM病原体的最有效的抗菌剂。然而，很少有人知道的分子机制，调节该分子的表达NTHi。我们的假设是NTHi通过激活中耳上皮细胞中的特异性信号通路上调β-防御素2。这与我们的长期目标一致，即研究表征良好的抗微生物先天免疫分子的表达并阐明其在OM发病机制中的作用。 为了实现我们的目标，我们将1）鉴定NTHi诱导的p-防御素2在体外和体内上调所需的上皮表面受体和受体相关的衔接子组分，2）确定MKK 3/6-p38 a/β信号通路是否参与介导NTHi诱导的p-防御素2上调，3）确定MKK 3/6-p38 a/β信号通路是否参与NTHi诱导的p-防御素2上调。（3）证明NTHi和IL-1 α可以通过不同的信号传导途径协同上调β-防御素2的表达。通过发现通过NTHi调节β-防御素2表达的信号通路，我们可能能够鉴定可用于将该分子在咽鼓管鼓室中的表达提高到治疗水平的分子靶标。

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.