Cytokine Inflammatory Mediators and Mucin Regulation in Middle Ear Epithelium

描述(申请人提供)：中耳炎(OM)是美国因病就医的儿科患者中最常见的诊断[1-2]，影响5岁以下所有儿童的90%以上[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，可导致言语、语言、教育和其他发育迟缓[6]。OM的治疗也消耗了大量的医疗资源，因为OM每年在美国的医疗支出约为50亿美元，是幼儿外科手术的最常见原因[4，7-8]，并与危及生命的并发症有关，如脑膜炎和脑脓肿形成[9-10]。鉴于这些因素，需要通过基础科学研究更彻底地了解OM，以提供潜在的新颖和有效的干预措施。具体地说，由中耳粘膜(MEM)产生的凝胶形成粘蛋白(GFM)被认为是慢性OM儿童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起着至关重要的作用。在了解粘蛋白在MEM中的调节方面取得的进展很少，在将实验室结果与OM患者的床边观察联系起来方面更是如此。回答我们的中心假设提出的问题，即特定的宿主和病原体因素影响中耳粘膜的变化，从而调节中耳的GFM，将使我们对ME粘蛋白的功能和调节与OM发病机制的理解有显著的提高。目前的建议将包括来自慢性OM儿童的临床标本、动物模型和体外细胞培养模型，并利用分子技术来回答这些基本问题：1)特异性GFM与儿童听力损失有什么关系；2)慢性OM儿童的MEM是否有可测量的变化与GFM的变化相关？3)抗生素治疗对GFM有意义的影响吗？4)ME间隙中生物膜的形成对GFM有什么影响？5)在慢性OM患者中，是否有任何主要的OM病原体：NTHI、SP或Mcat不同地调节GFM的产生，6)水通道蛋白5是否影响GFM的调节；7)GFM的表达与OM病原体的多菌感染之间是否存在相关性？通过这项提议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来开发OM发病机制的新干预措施。 与公共卫生相关：耳朵感染几乎影响所有儿童，是我们医疗保健系统的昂贵负担，也是导致儿童听力损失的最常见原因；导致潜在的发育困难。粘蛋白是一些儿童在耳部感染后在鼓膜后面积聚的液体，会导致听力损失。了解这些粘蛋白在慢性耳朵感染儿童中是如何形成的，并开发新的治疗和护理这些儿童的方法，有可能减少患有听力损失和与这种疾病相关的其他困难的儿童。

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. PUBLIC HEALTH RELEVANCE: Ear infections affect almost all children, are an expensive burden on our health care system and are the most common cause of hearing loss in children; leading to potential developmental difficulties. Mucins are the fluids that build up behind the eardrums in some children after ear infections and cause the hearing loss. Understanding how these mucins form in children with chronic ear infections and developing new ways to treat and care for these children has the potential to lead to fewer children with hearing loss and other difficulties associated with this disease.