Innate Immunity in Otitis Media Pathogenesis

中耳炎发病机制中的先天免疫

• 批准号: 7116886
• 负责人: David J. Lim
• 金额: $ 33.2万
• 依托单位: HOUSE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-10 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7116886
• 关键词: Haemophilus influenzae; RNA interference; Streptococcus pneumoniae; bactericidal immunity; binding proteins; biological signal transduction; defensins; disease /disorder etiology; drug interactions; gene expression; genetically modified animals; immunity; interleukin 1; laboratory mouse; lysozyme; mitogen activated protein kinase; otitis media; receptor expression; tissue /cell culture; toll like receptor; tympanum

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.

描述（由申请人提供）：在普通感冒之后，中耳炎（OM）或中耳的炎症是最常见的疾病，导致对医生的探视和最常见的儿童听力障碍原因。在过去的几十年中，在引起OM的细菌中，在全球范围内观察到抗生素耐药性令人震惊。然而，迄今为止，尚未开发出其他疗法来应对这种疾病。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，必须了解控制构成拟南芥的第一道防御病原体的第一线的先天免疫分子表达的分子机制，并确定是否可以利用这些机制来预防或治疗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，关于通过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的特定信号通路来上调β-防御素2。这符合我们的长期目标，即研究特征良好的抗菌先天免疫分子的表达并阐明其在OM发病机理中的作用。 朝着我们的目标，我们将1）确定NI-THI诱导的P-Defensin 2上调的上皮表面受体以及与受体相关的衔接子成分在体外和体内上调2）确定MKK3/6-P38A/BetA信号通路是否涉及Nththi-Fefensin and 3），并介导了3），并介导了3次探测（3）。 NTHI和IL-1Alpha可以通过不同的信号通路协同上调β-防御素2的表达。通过发现通过NTHI调节β-防御素2表达的信号传导途径，我们可能能够鉴定出可用于提高该分子表达对tubotympanum中治疗水平的表达的分子靶标。