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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：
7251979
负责人：
JOSEPH E KERSCHNER
金额：
$ 36.78万
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7251979
关键词：
Acute Address Adherence Adverse effects Affect Animal Model Animals Antibodies Antimicrobial Resistance Appearance Area Arthritis Asthma Award Basic Science Behavior Binding Binding Proteins Biology Biopsy Cavia Cell Adhesion Cell Culture Techniques Cell Differentiation process Cell Line Cell physiology Cells Cervical Characteristics Child Childhood Chinchilla (genus)Chronic Chronic Bronchitis Chronic Disease Clinical Compatible Complex Condition Crohn&apos s disease Cultured Cells Data Defense Mechanisms Desmosomes Development Diagnosis Disease Dose Ear Ear Diseases Electron Microscopy Electrons Endotoxins Ensure Epithelial Epithelial Cells Epithelial Physiology Epithelium Eustachian Tube Evaluation Event Exhibits Experimental Models Exposure to Family Functional disorder Funding Future Gel Gene Expression Gene Expression Regulation Gene Proteins Gene Transfer Genes Genetic Genomics Glycoproteins Goblet Cells Grant Haemophilus influenzae Harvest Health Health Expenditures Hemophilus Herpes zoster disease Histocompatibility Testing Histologic Histology Host Defense Human Human Development IL8 gene Immune Immunohistochemistry In Vitro Infection Inflammation Inflammation Process Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interleukin-1 Interleukin-6 Interleukin-8 Intervention Investigation Karyotype determination procedure Knowledge Laboratories Lead Leukocytes Link Liquid substance Listeria monocytogenes Literature Local Therapy Localized Lung MCAM gene MUC5AC gene MUC5B gene Measures Mediating Mediator of activation protein Membrane Methods Microscopic Microscopy Modeling Molecular Molecular Models Morbidity - disease rate Muc 2 protein Mucin 1 protein Mucin-1 Staining Method Mucin-2 Staining Method Mucins Mucociliary Clearance Mucous Membrane Mucous body substance Nature Nose Numbers Operative Surgical Procedures Oral cavity Organism Otitis Otitis Media Otitis Media with Effusion Pancreatitis Pathogenesis Pathologic Pathology Pathway interactions Patients Peer Review Personal Satisfaction Physicians Physiological Physiology Play Predisposition Preparation Prevalence Primary Cell Cultures Principal Investigator Process Production Property Proteins Publications Publishing Pus Range Rate Rattus Reagent Recombinants Recording of previous events Recurrence Regulation Relative (related person)Reporting Research Resolution Respiratory Mucin Rheumatoid Arthritis Rodent Model Role Salivary Glands Scientist Secretory Cell Secretory Vesicles Sepsis Serous Shock Signal Pathway Signal Transduction Pathway Solutions Somatic Cell Specimen Staging Staining method Stains Streptococcus pneumoniae Stress Structure Structure of respiratory epithelium TNF gene Tandem Repeat Sequences Techniques Therapeutic Therapeutic Intervention Thinking Time Tissue Harvesting Tissues Tracheal Epithelium Transformed Cell Line Translating Translations Transudate Tube Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors Tumorigenicity Tympanostomy Ulcerative Colitis United States Up-Regulation Variant Viscosity Visit Work airway epithelium anakinra bronchial epithelium cancer cell cell type cellular microvillus cilium biogenesis clinical efficacy clinically significant cohort comparative concept cytokine effusion eustachian tube orifice gastrointestinal microvillus hearing impairment human TNF protein human disease human study human tissue immortalized cell immune function improved in vitro Model in vivo in vivo Model inhibitor/antagonist innovation insight interest microbial middle ear mortality mucoid novel pathogen polypeptide pressure prevent progenitor programs research study respiratory respiratory protein response tissue culture transmission process

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，并且粘蛋白与慢性耳部疾病、中耳防御机制和病原体活力相关。Pi正在进行的NIDCD K 08奖项期间进行的研究得出的数据表明，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，同时上调龙猫模型中的凝胶形成粘蛋白。然而，正在进行的工作和本提案中提出的初步数据表明，呼吸上皮（如中耳）中的粘蛋白生理学比最初假设的更复杂。这部分地与许多最近鉴定的粘蛋白基因有关，粘蛋白基因具有独特的性质，并且初步数据表明其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关于细胞因子、中耳粘蛋白及其相互作用的几个基本问题：1）哪些粘蛋白基因在灰鼠和人中耳上皮细胞培养物中表达，它们是否对应于体内中耳粘蛋白基因表达？2)炎性细胞因子TNF-α、IL-1 β、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)这些炎性细胞因子的作用能被抑制剂限制吗？和4）与非中耳炎患者相比，中耳炎患者中耳组织中粘蛋白基因的相对表达是什么，这与本研究中提出的实验模型相比如何？对这些问题的回答将拓宽我们对中耳炎-粘蛋白相互作用的理解，将提供适用于灰鼠和人类模型的信息，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知识，将提供关于有和没有中耳炎病史的患者中粘蛋白表达的具体临床信息，并将提供一个平台，以建立未来的研究，中耳粘蛋白的功能。在详细了解中耳炎细胞因子-粘蛋白相互作用后，可以开发用于确定通过调节细胞因子和粘蛋白途径对中耳炎进行新干预的模型。此外，中耳粘蛋白生理学的表征可能导致在中耳和中耳炎中的粘膜防御的理解的进步。这些目标的完成不仅可以更清楚地了解中耳炎的病理学，还可以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部疾病治疗的进展，慢性耳部疾病仍然是儿童最常见的疾病之一。