This application is a response to The National Institute on Deafness and Other Communication Disorders (NIDCD) issued PA-09-228 encouraging R01 applications that focus on Proteomics in Auditory Developmental and Disease Processes. Otitis media (OM), the most prevalent chronic childhood disorder, is associated with staggering public health care costs. It is a disease of the middle ear space characterized by acute infectious injury and inflammation, acute OM (AOM), progressing to chronic epithelial mucoid fluid secretion, i.e. chronic OM (COM). The OM continuum from acute to chronic is triggered by infectious or noxious stimuli that result in thickening of middle ear epithelia (MEE) and leads to self-sustaining chronic inflammation and mucous hypersecretion. This in turn often leads to medical treatment failure, and the placement of surgical tympanostomy tubes - the most common surgical procedure of children. In published and preliminary data, we have begun to characterize the molecular progression of OM events. We have recently shown that the hyperviscous mucus in COM is characterized by an overabundance of MUC5B mucin, a major airway secreted mucin. Through a gene expression profiling approach in a mouse model of acute OM based on middle ear inoculation of Non-typeable Hemophilus Influenza (NTHi) (currently the most common human AOM pathogen), we identified the pro-inflammatory cytokine Cxcl2 as markedly and acutely upregulated. Additionally, we observed that the middle ear epithelium chronically trans-differentiated into a thicker, pseudostratified state after repeatd NTHi lysate exposure. Here, we propose an interdisciplinary approach to understanding, and then intervening in, the molecular pathobiology of COM. We hypothesize that AOM, triggered by an inflammatory event (NTHi), activates expression of Cxcl2 and downstream expression of Muc5b/MUC5B, resulting in progression to chronic otitis media.
We first aim to use a proteomic and cytokine secretome profiling approach to determine the in vitro effects of NTHi on a middle ear epithelial pro- inflammatory response, gaining important information that would complement our preliminary in vivo data. Secondly, we will analyze the effects of key inflammatory mediators identified in Aim 1 (predictably Cxcl2 and/or NF?B) on the expression of Muc5b. Finally, we will then aim to intervene at key molecular steps in the process (predictably Cxcl2, and/or NF?B) to halt progression to COM and middle ear Muc5b over-expression. The combination of our findings should result in a better understanding of pathways in OM pathophysiology and are likely to reveal novel molecular therapeutic targets that when modulated may help abate progression of AOM to COM.
Otitis Media (OM) is one of the most frequent disorders in children requiring physician visits. It is a disease of the middle ear space characterized by acute infectious injury and inflammation, acute OM (AOM), progressing to chronic epithelial mucoid fluid secretion, i.e. chronic OM (COM). In this application, using a proteomic profiling approach, we aim to interrogate how pathologically relevant acute infectious stimuli result in a cascade of inflammatory mediator up- regulation which in turn ultimately lead to middle ear epithelial metaplasia and inappropriate over-expression of mucins. Currently no medications exist to treat COM effectively. An understanding of the molecular mechanisms behind the progression of acute middle ear infection to chronic OM may radically change the way the disease is treated, especially if novel molecular targets are identified. Continuation Page
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