Disease in the middle ear (otitis media) caused by germs (bacteria) is one of the most common reasons why children get ill and visit their doctor. It causes sore ears that affect most children at least once before the age of five. The disease can become prolonged with constant fluid in the ear that leads to problems with hearing and often learning difficulties for the affected children. At MRC Harwell Institute we investigate ear disease and the genes associated with it using the mouse. We study the ears of mice with genetic mutations that make them more likely to get otitis media to discover the mechanisms and physiology underlying the disease and to test better ways to treat the disease. We can infect the middle ear of these mice in much the same way that the germs infect in children. Our studies in the mouse help us to better understand what things are important and combine to cause and prolong this infection, and can give us fresh ideas on how to lessen disease. Our successful mouse models allow us to test new ways that could prevent or treat the equivalent middle ear infection in children.

The mouse is widely used as a model for human disease. Our aim is to provide computational tools and analytical results that help us to better understand the functions of mouse genes and, threfore, their human couterparts. We have two main areas of interest. The first of these is the collection, storage and analysis of mouse phenotype data. Projects to systematically characterise the phenotypes of mice that have had single genes disabled have started and are likely to become increasingly important in the next few years. We have developed mechanisms for collecting, storing and displaying this data and have a strong interest in the representation of phenotype data using ontologies and in its analysis. With the advent of new, high-throughput technoligies for DNA sequencing we have the opportunity to understand in much greater detail the mutations giving rise to individual phenotypic changes and their effects on protein function and gene regulation. We are developing software to facilitate this analysis in the context of the Unit’s research.

Otitis media is an important medical condition affecting the middle ear. There are a number of distinct forms of the disease and all cause ill health and have considerable health care costs. 80% of children will suffer one or more episodes of earache before the age of three and this condition is one of the most common reasons for taking child to see their GP. In most cases these painful episodes of earache resolve spontaneously. However, about 10% of children go on to have persistent ear problems and one particularly common condition is known as 'glue ear'. Although the symptoms of pain and fever go away, the child may suffer significant hearing loss. Glue ear is the most common form of childhood hearing loss. It occurs as a result of fluid accumulation in the middle ear space behind the eardrum. The fluid occupies a space that is normally air-filled in the healthy ear and this interferes with sound transmission through the three small bones that link the eardrum to the inner ear. Hearing loss manifests itself in delays in the child's language development and can result in learning and behavioral problems. Currently the only effective treatment is surgery to place a grommet in the eardrum. Grommet surgery is the most common surgical procedure performed on children. The NHS performs 30,000 grommet surgeries per year. Grommet surgery is not always effective, but there are currently no alternative beneficial medical treatments. In this work we will use an animal model of chronic otitis media to explore new medical treatments for glue ear. Previously we have has shown that a molecular pathway involved in the response to low oxygen conditions is important in the development of disease and similar process occurs in children. Our plan is to use existing drugs that have been developed to target these pathways and look at their ability to moderate hearing loss in our animal model. The particular drug that will be used is Saracatinib that Astra Zeneca developed to treat cancer. Cancer is very different medical condition to glue ear but both diseases share an underlying disease process associated with blood vessel growth and fluid leakiness. In the ear we hypothesize the accumulation of glue and fluid is driven by the leakiness of the blood vessels that line the middle ear space. The use of anti-cancer drugs in children is restricted to serious life-threatening disease because of the potential for significant side effects when given as a tablet. The aim of this project is to investigate the potential of medicating the ear directly so that the drug is delivered to where it is needed to prevent hearing loss. It will be necessary to develop a formulation of drug that will release drug over periods of up to one month. The response to the treatment will be measured in hearing tests and measuring the action of the drug on the blood vessels of the ear. We will also investigate whether drug levels in the blood are sufficiently low after medicating the ear to make them safe for use. If our work is successful it will open up new avenues of research in medical treatment of ear disease. There is a major effort to find new ways of medicating the ear and if this is achieved there will be great interest from pharmaceutical companies to discover new uses for their existing drugs, as well as developing new drugs. This has the potential to revolutionize the treatment of chronic middle ear disease and shift treatment away from surgery to medical treatments such as eardrops that could be prescribed by a GP.

Mice are the pre-eminent animal models for human genetics and disease. We are studying the genetics of susceptibility to bacterial infection in mice and using chemically induced mutations to improve our basic biological understanding of gene function in health and disease. The main bacterium we study is Streptococcus pneumoniae, which causes glue ear, pneumonia, and bacterial meningitis in humans; despite vaccine and antibiotic therapies, infections caused by this bacterium may still be deadly.||We construct maps of the mouse genome, supplying different levels of map detail. Some of the maps indicate the general lie of the land, like a physical map, whereas other maps indicate the presence of features such as towns. In this analogy, towns represent the variations in specific genes associated with traits or phenotypes. Our research helps in finding these variations, so that we can then study how they influence susceptibility to bacterial infection.||Almost all mouse genes have a human counterpart and so genes controlling infection in mice are likely to play a similar role in humans. We expect, therefore, to improve our understanding of the basic biology of infection in humans and mice. Furthermore, we may contribute to improvements in prevention and treatment of infection.

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