Cytokine Inflammatory Mediators and Mucin Regulation in Middle Ear Epithelium

描述（申请人提供）：中耳炎（OM）是美国因疾病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]，是儿童抗菌治疗的最常见适应症[5]，是幼儿听力损失的最常见原因，并可导致言语，语言、教育和其他发育迟缓[6]。OM的治疗还消耗了大量的医疗保健资源，因为OM每年在美国的医疗保健支出中约占50亿美元，是幼儿外科手术的最常见原因[4，7 -8]，并与危及生命的并发症如脑膜炎和脑脓肿形成有关[9- 10]。鉴于这些因素，需要通过基础科学研究更深入地了解OM，以提供潜在的新颖有效的干预措施。具体而言，由中耳粘膜（MEM）产生的凝胶形成粘蛋白（GFM）已知是在患有慢性OM的儿童中发展的听力损失的主要原因，并且粘蛋白也已知在ME粘膜保护功能和免疫中至关重要。在了解MEM中粘蛋白的调节方面取得的进展很少，在将实验室发现与OM患者的床边观察相关联方面取得的进展更少。我们的中心假说提出的问题，即特定的宿主和病原体因素影响粘膜的变化，以调节GFM在中耳将允许我们的理解ME粘蛋白的功能和调节OM发病机制的显着增强。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，并采用分子技术回答这些基本问题：1）特定GFM与儿童听力损失的关系是什么，2）慢性OM儿童的MEM是否存在与GFM变化相关的可测量变化？3)抗生素治疗对GFM是否有意义？，4)ME空间中生物膜形成对GFM的影响是什么？，5)在慢性OM患者中，任何主要OM病原体：NTHi，SP或Mcat是否差异调节增加的GFM产生，6）水通道蛋白5是否影响GFM调节和7）GFM表达与OM病原体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，并将继续推进我们的长期目标，即通过调节粘蛋白产生途径开发OM发病机制的新干预措施。

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.