Otitis media is one of the largest public health problems of young children. Otitis media is thought to be a multifactorial condition that can be induced by a variety of inciting events. However, once initiated, otitis media often converges on a final common pathway of inflammation, effusion and tissue hyperplasia that in turn can produce temporary and even permanent hearing loss. Upon resolution of otitis media the hyperplastic middle ear mucosa can recover to a condition at or close to its original structure, although permanent changes including fibrosis and osteoneogenesis sometimes occur The long-term goal of this project is to understand host responses in the middle ear during otitis media, with a particular focus on the transformation of the middle ear mucosa from a resting state into a highly active, hyperplastic structure that contributes to both host defense and pathogenesis. Data obtained during the current period of support has led us to propose a novel, dysinhibition model of otitis media. According to this model, proteins expressed by the resting middle ear mucosa normally inhibit cell proliferation and hyperplasia. Inflammation leads to a reduction in expression of these proteins. This in turn dysinhibits mucosal cells and enables tissue growth. Growth is actuated by the concurrent expression of growth factors and the dysinhibition of cell signaling pathways that mediate tissue response. Re-establishment of inhibition contributes to otitis media recovery, while failure of re-inhibition contributes to otitis media persistence. We will test this model by evaluating the expression of genes proposed to mediate inhibition, by mis-expressing these genes in the middle ear mucosa to induce or block hyperplasia, by evaluating gene knockout mice when available, and by comparing the expression of inhibitory genes in persistent versus acute otitis media. PUBLIC HEALTH RELEVANCE: Otitis media is one of the most common diseases of childhood, resulting in more physician visits and surgeries than any other pediatric disorder. Persistent or recurrent otitis media can damage the middle or inner ear and cause permanent hearing loss. The goal of the proposed research is to identify targets for potential new therapies in this disease.