Cytokine Inflammatory Mediators and Mucin Regulation in Middle Ear Epithelium

中耳上皮细胞因子炎症介质和粘蛋白调节

• 批准号: 8874947
• 负责人: JOSEPH E KERSCHNER
• 金额: $ 32.07万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8874947
• 关键词: Acute; Affect; Age; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Basic Science; Brain Abscess; Cell Culture Techniques; Cells; Child; Child Care; Chinchilla (genus); Chronic; Clinical; Data; Development; Developmental Delay Disorders; Diagnosis; Disease; Epithelium; G-Protein-Coupled Receptors; Gel; Gene Expression; Genetic Transcription; Goals; Health Expenditures; Healthcare; Healthcare Systems; Hearing; Hypertrophy; Immunity; In Vitro; Infection; Infiltration; Inflammation Mediators; Inflammatory; Intervention; Investigation; Knock-out; Knockout Mice; Laboratory Finding; Language; Lead; Life; Liquid substance; MUC5AC gene; MUC5B gene; Measurable; Meningitis; MicroRNAs; Microbial Biofilms; Modeling; Molecular; Muc 2 protein; Mucins; Mucous Membrane; Mus; Operative Surgical Procedures; Otitis Media; Pathogenesis; Pathway interactions; Patients; Physicians; Production; Regulation; Research; Resources; Specimen; Speech; Techniques; Time; Tympanic membrane; United States; Up-Regulation; Visit; antimicrobial; aquaporin 5; cytokine; ear infection; hearing impairment; microbial; middle ear; novel; pathogen; pediatric patients; research study; response; water channel

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.

描述（由申请人提供）：耳炎培养基（OM）是在美国拜访医生患疾病医生[1-2]的小儿患者中最常见的诊断[1-2]，到5岁[3-4]的所有儿童中，所有儿童中有90％以上是儿童抗菌治疗的最常见指示，是儿童抗菌治疗的最常见的损失[5]，是年轻儿童的造成损失，是年轻人和其他语言的教育，并导致了6个教育，并导致了6个教育[5]。 OM的治疗还消耗了大量的医疗保健资源，因为OM在美国的医疗保健支出中每年约有50亿美元，这是幼儿手术程序的最常见原因[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]。鉴于这些因素，需要通过基础科学调查对OM进行更透彻的了解，以提供潜在的新颖和有效的干预措施。具体而言，中耳粘膜（MEM）产生的凝胶形成的粘蛋白（GFM）是听力损失的主要原因，在慢性OM和粘蛋白的儿童中发展为听力损失，在我的粘膜保护功能和免疫力中也非常重要。在了解MEM中粘蛋白的调节方面，在将实验室发现与患有OM患者的床边观察相关联时，几乎没有实现的目标。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会影响粘膜变化以调节中耳中的GFM，将使我们理解我的粘蛋白功能和与OM发病机理有关的调节显着增强。当前的建议将包括来自患有慢性OM，动物模型和体外细胞培养模型的儿童的临床标本，并采用分子技术来回答这些基本问题：1）特定的GFM与儿童听力丧失的关系是什么关系，2）2）儿童的MEM与持续的OM与GFM中的变化相关的儿童的MEM是否有意义？生物膜形成对ME空间中GFM的影响？，5）对慢性OM患者的影响，任何主要的OM病原体：NTHI，SP或MCAT是否会差异调节GFM的产生增加，6）Aquaporin 5 Impact GFM调节和7）是否存在GFM表达和Omicrobial Inctuction Omomial pathogement omomial pathogemengial omomial pathogengemens ot Omicrobial感染之间的相关性吗？通过该提案产生的数据将为这些问题提供答案，并将继续促进我们通过调节粘蛋白生产途径在OM发病机理中开发新的干预措施的长期目标。