Cytokine Inflammatory Mediators and Mucin Regulation in Middle Ear Epithelium

描述（由申请人提供）：中耳炎（OM）是在美国就诊的儿科患者中最常见的诊断[1-2]，影响超过90%的5岁儿童[3-4]，是儿童抗微生物治疗最常见的适应症，是幼儿听力损失最常见的原因，可导致言语、语言、教育和其他发育迟缓[1- 4]。OM的治疗也消耗了大量的医疗资源，因为OM在美国每年的医疗支出约为50亿美元，是幼儿外科手术的最常见原因[4,7-8]，并且与危及生命的并发症如脑膜炎和脑脓肿形成有关[9- 10]。考虑到这些因素，需要通过基础科学调查更彻底地了解OM，以提供潜在的新颖有效的干预措施。具体来说，由中耳粘膜（MEM）产生的凝胶形成粘蛋白（GFM）是慢性OM患儿听力损失的主要原因，粘蛋白在ME粘膜保护功能和免疫中也至关重要。在发展对MEM中粘蛋白调节的理解方面取得的进展很少，在OM患者的实验室结果与床边观察的相关性方面取得的进展更少。回答我们的中心假设所提出的问题，即特定的宿主和病原体因素影响粘膜变化以调节中耳GFM，将大大增强我们对ME粘蛋白功能和与OM发病机制相关的调节的理解。目前的提案将包括慢性OM儿童的临床标本，动物模型和体外细胞培养模型，并采用分子技术来回答这些基本问题：1)特异性GFM与儿童听力损失的关系是什么？ 2)慢性OM儿童的MEM是否存在可测量的变化与GFM的变化相关？3)抗生素治疗对GFM是否有显著影响？4) ME空间生物膜的形成对GFM有何影响？5)慢性OM患者的OM原发病原体：NTHi、SP或Mcat是否对GFM的产生有差异调节？ 6)水通道蛋白5是否影响GFM的调节？ 7)GFM的表达与OM病原菌的多微生物感染之间是否存在相关性？通过该提案产生的数据将为这些问题提供答案，并将继续推进我们通过调节粘蛋白产生途径开发新的OM发病机制干预措施的长期目标。

DESCRIPTION (provided by applicant): Otitis media (OM) is the most common diagnosis in pediatric patients who visit physicians for illness in the United States [1-2], affects more than 90% of all children by the age of 5 [3-4], is the most common indication for antimicrobial therapy in children [5], is the most common cause of hearing loss in young children and can lead to speech, language, educational and other developmental delays [6]. Treatment of OM also consumes significant health care resources as OM is responsible for approximately $5 billion annually in health care expenditures in the U.S., is the most common cause for surgical procedures in young children [4,7-8], and is associated with life-threatening complications such as meningitis and brain abscess formation [9- 10]. Given these factors, a more thorough understanding of OM through basic science investigation is required to provide potential novel and efficacious interventions. Specifically, gel-forming mucins (GFM), produced by middle ear mucosa (MEM), are known to be the primary cause of hearing loss which develops in children with chronic OM and mucins are also known to be critically important in ME mucosal protective functions and immunity. Very little has been achieved in developing an understanding of the regulation of mucins in MEM and even less in correlating laboratory findings to bedside observations in patients suffering from OM. Answering the questions posed by our Central Hypothesis that specific host and pathogen factors influence mucosal changes to regulate GFM in the middle ear will allow significant enhancement in our understanding ME mucin function and regulation in relation to OM pathogenesis. The current proposal will include clinical specimens from children with chronic OM, animal models and in vitro cell culture models and employ molecular techniques to answer these fundamental questions: 1) What is the relationship of specific GFM to hearing loss in children, 2) Are there measurable changes in the MEM of children with chronic OM that correlate with changes in GFM?, 3) Does utilization of antibiotic therapy have a meaningful effect on GFM?, 4) What is the impact of biofilm formation on GFM in the ME space?, 5) In patients with chronic OM, do any of the primary OM pathogens: NTHi, SP or Mcat differentially regulate increased GFM production, 6) Does aquaporin 5 impact GFM regulation and 7) Is there a correlation between GFM expression and polymicrobial infection of OM pathogens? Data generated through this proposal will provide answers to these questions and will continue to advance our long-term goal of developing novel interventions in OM pathogenesis through modulation of mucin production pathways.