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

基本信息

批准号：
7888212
负责人：
JOSEPH E KERSCHNER
金额：
$ 35.94万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888212
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

项目摘要

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）：本提案的目的是进一步阐明中耳上皮中细胞因子和粘蛋白的作用和相互关系。已经证明，中耳炎是细胞因子依赖性过程，粘蛋白与慢性耳病、中耳防御机制和病原体活力相关。 Pi 正在进行的 NIDCD K08 奖期间进行的研究数据表明，细胞因子 TNF-a、11-1B 和 IL-6 上调粘蛋白分泌，并促进粘蛋白基因的差异表达，并上调龙猫模型中的凝胶形成粘蛋白。然而，正在进行的工作和该提案中提出的初步数据表明，呼吸道上皮（例如中耳）中的粘蛋白生理学比最初假设的更为复杂。这部分与最近发现的许多粘蛋白基因有关，这些基因具有独特的特性，初步数据表明这些基因在中耳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）哪些粘蛋白基因在龙猫和人类中耳上皮细胞培养物中表达，它们是否与体内中耳粘蛋白基因表达相对应？ 2）炎症细胞因子TNF-a、11-1p、IL-6和IL-8在基因组和蛋白质水平上对中耳上皮粘蛋白有什么影响？ 3）这些炎症细胞因子的作用可以通过抑制剂来限制吗？ 4) 与非中耳炎患者相比，中耳炎患者中耳组织中的相对粘蛋白基因表达是多少？与本研究中提出的实验模型相比如何？这些问题的答案将拓宽我们对细胞因子-粘蛋白中耳相互作用的理解，将提供适用于龙猫和人类模型的信息，将扩展我们对细胞因子和粘蛋白在中耳炎病理生理学中的功能的了解，将提供具体的临床信息关于有或没有中耳炎病史的患者的粘蛋白表达，并将提供一个平台来建立未来研究中耳粘蛋白的特定功能。在详细了解中耳细胞因子-粘蛋白相互作用后，可以开发通过调节细胞因子和粘蛋白途径来确定中耳炎新干预措施的模型。此外，中耳粘蛋白生理学的表征可能会促进对中耳粘膜防御和中耳炎的理解的进展。这些目标的完成很可能不仅能让人们对中耳炎的病理学有更清晰的了解，而且将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，并将导致中耳炎和慢性耳病治疗的进展。它仍然是儿童期最流行的疾病之一。