CYTOKINE INFLAMMATORY MEDIATORS AND MUCIN REGULATION IN MIDDLE EAR EPITHELIUM

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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.