Acute otitis media, sometimes known as “glue ear”, is the most common bacterial infection in children and by 1 year of age about 60% of children will have had one episode. In some cases, children develop a chronic condition, which, despite the infection being cured, the “glue” doesn’t go away and causes deafness. In an inherited mouse model of chronic glue ear the causative mutation has been shown to be in a gene encoding a transcription factor, Evi1.
The EVI1 protein has multiple domains, can repress or enhance expression of target genes and interact with many other proteins. Indeed, the multiplicity of known and potential interactions is a challenge to determining the role of the mutation. There were clues, however, as to how this mutation might lead to disease from differences in phenotype e.g. mutant mice raised in a “clean” SPF animal facility were less likely to become deaf than those kept in the older, “dirty” animal house.
Did this mean that gene-environment interactions e.g. between immune system and microbes, influence disease susceptibility? It was also known that mutant mice showed high levels of influx of neutrophils into their middle ear cavities (inflammation), but it was unclear whether EVI1 was acting directly or indirectly in this process. Possible answers to these questions came recently from studies in cultured cells, showing that EVI1 can act as an inhibitor of one of the key proteins regulating inflammation, another transcription factor, nuclear factor kappa B (NFkB). EVI1 binds to to one of the subunits of NFkB and interferes with a critical protein modification, acetylation. However, EVI1 does not acetylate proteins directly, so other factors must be involved. What were those other factors?
I combined public and unpublished data using literature searches and open source software e.g. iRefWeb in order to identify steps in the NFkB signalling pathways that might be disturbed by the mutation in EVI1. The novel target proteins and starting points for drug development I discovered are suitable for testing in this preclinical model of chronic otitis media.
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