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: 7636818
• 负责人: JOSEPH E KERSCHNER
• 金额: $ 36.3万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7636818
• 关键词: Address; Affect; Award; Biology; Biopsy; Cell Culture Techniques; Childhood; Chinchilla (genus); Chronic; Clinical; Complex; Data; Defense Mechanisms; Disease; Dose; Ear Diseases; Epithelial; Epithelial Cells; Epithelial Physiology; Epithelium; Exhibits; Experimental Models; Functional disorder; Funding; Future; Gel; Gene Expression; Gene Expression Regulation; Genes; Genomics; Glycoproteins; Human; IL8 gene; Inflammation Mediators; Inflammatory; Interleukin-1; Interleukin-6; Interleukin-8; Intervention; Investigation; Knowledge; Lead; Liquid substance; MUC5AC gene; MUC5B gene; Modeling; Muc 2 protein; Mucin 1 protein; Mucin-1 Staining Method; Mucin-2 Staining Method; Mucins; National Institute on Deafness and Other Communication Disorders; Otitis Media; Pathology; Pathway interactions; Patients; Physiology; Process; Property; Proteins; Recording of previous events; Regulation; Relative (related person); Role; Scientist; Structure of respiratory epithelium; Time; Tissues; Transformed Cell Line; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; Work; cohort; cytokine; in vivo; inhibitor/antagonist; interest; middle ear; novel; pathogen; response

DESCRIPTION (provided by applicant): The objective of this proposal is to further elucidate the role and interrelationship of cytokines and mucins in middle ear epithelium. It has been demonstrated that otitis media is a cytokine dependent process and that mucins are associated with chronic ear disease, middle ear defense mechanisms and pathogen viability. Data resulting from studies conducted during the Pi's ongoing NIDCD K08 award has demonstrated that the cytokines TNF-a, 11-1B and IL-6 upregulate mucin secretion and promote a differential expression of mucin genes with upregulation of gel-forming mucins in a chinchilla model. However, ongoing work and preliminary data presented in this proposal has demonstrated that mucin physiology in respiratory epithelium, such as the middle ear, is more complex than initially hypothesized. This is partially related to numerous recently identified mucin genes, which have unique properties, and which preliminary data suggest also have important functional roles in middle ear epithelial physiology and pathophysiology. This current proposal seeks funding to address several fundamental questions regarding cytokines, middle ear mucins and their interactions: 1) Which mucin genes are expressed in chinchilla and human middle ear epithelial cell cultures and do they correspond to in vivo middle ear mucin gene expression? 2) What effect do the inflammatory cytokines TNF-a, 11-1 p, IL-6 and IL-8 have on middle ear epithelium mucins at both the genomic and protein level? 3) Can the effects of these inflammatory cytokines be limited by inhibitors? and 4) What is the relative mucin gene expression in middle ear tissue from patients with otitis media compared with patients without otitis media and how does this compare with the experimental models proposed in this investigation? Answers to these questions will broaden our understanding of cytokine-mucin middle ear interactions, will provide information that is applicable to both chinchilla and human models, will extend our knowledge of the function of cytokines and mucins in otitis media pathophysiology, will provide specific clinical information regarding mucin expression in patients with and without otitis media history and will provide a platform to build future studies examining specific functionality of middle ear mucins. After a detailed understanding of middle ear cytokine-mucin interactions, models for determining novel interventions for otitis media through modulation of cytokine and mucin pathways can be developed. In addition, characterization of middle ear mucin physiology may lead to advances in the understanding mucosal defenses in the middle ear and otitis media. It is likely that completion of these aims will not only provide a clearer understanding of the pathology in otitis media but will benefit other scientists interested in middle ear biology, physiology and pathophysiology and will lead to advances in the treatment of otitis media and chronic ear disease which continues to be among the most prevalent diseases of childhood.

描述（由申请人提供）：该提案的目的是进一步阐明细胞因子和粘蛋白在中耳上皮中的作用和相互关系。已经证明中耳炎是一个依赖细胞因子的过程，粘蛋白与慢性耳部疾病，中耳防御机制和病原体生存能力有关。在PI持续进行的NIDCD K08奖中进行的研究产生的数据表明，细胞因子TNF-A，11-1B和IL-6上调了粘蛋白分泌，并促进了粘蛋白基因在Chinchilla模型中粘蛋白上调的粘蛋白基因的差异表达。但是，该提案中介绍的正在进行的工作和初步数据表明，呼吸性上皮（例如中耳）中的粘蛋白生理比最初假设的更为复杂。这与众多最近鉴定出的粘蛋白基因部分有关，这些基因具有独特的特性，并且初步数据表明在中耳上皮上皮生理学和病理生理学中也具有重要的功能作用。目前的提案寻求资金来解决有关细胞因子，中耳粘蛋白及其相互作用的几个基本问​​题：1）哪些粘蛋白基因在Chinchilla和人类中耳上皮上皮细胞培养物中表达，并且它们是否与体内中耳粘蛋白基因表达相对应？ 2）炎性细胞因子TNF-A，11-1 P，IL-6和IL-8对中耳上皮粘液的基因组和蛋白质水平有什么影响？ 3）这些炎性细胞因子的作用是否受抑制剂的限制？ 4）与没有中耳炎的患者相比，中耳组织中中耳组织中的粘蛋白基因表达是什么？与此研究中提出的实验模型相比，这是什么？这些问题的答案将扩大我们对细胞因子粘液中耳相互作用的理解，将提供适用于丁香和人类模型的信息，将扩展我们对耳炎媒体病理生理学中细胞因子和粘蛋白功能的了解，将提供有关媒体媒体历史和不具有耳朵炎的患者的粘蛋白表达的特定临床信息，可为未来的ETER INDER ICK INCET培养培养精力培养特定的ETUIS，以构建特定的ETUIN，以培养特定的ETUIS。在详细了解中耳细胞因子 - 粘蛋白相互作用后，可以开发用于通过调节细胞因子和粘蛋白途径来确定中耳炎的新干预措施的模型。此外，中耳粘蛋白生理学的表征可能会导致理解中耳和中耳炎的粘膜防御能力的进步。这些目标的完成可能不仅可以更清楚地了解中耳炎中的病理学，而且会使其他对中耳生物学，生理学和病理生理学感兴趣的科学家受益，并将导致治疗中耳炎和慢性耳部疾病的进步，这仍然是最普遍的儿童疾病之一。