Neurogenin 3: regulation of protein stability.

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Diabetes results from loss or inactivity of cells, called islet cells, that produce insulin. One of the ways that we could treat diabetes is by replacing these cells using stem cells that have been instructed to turn into islets. Neurogenin 3 (NGN3) is a protein that drives formation of islets and the amount of NGN3 protein present in very important. We have found that NGN3 protein is unstable and is rapidly destroyed in the cells of the body. This proposal aims to look at the ways this destruction is controlled. When we understand this, we can make altered forms of NGN3 that are resistant to being broken down. In these intial studies, we will inject these stable forms of NGN3 into tadpoles to see if they are, indeed, present at higher levels and are, therefore, more active that the original protein. Tadpoles are excellent for this study as they are large, develop outside the mother and are easy to inject proteins into. Moreover, we already know that tadpoles respond to normal NGN3 so act as a useful system to test for increased NGN3 activity. We will then see if our altered NGN3s are also stable in mammalian cells in culture. These studies will pave the way for experiments to see if stabilised NGN3 can be added back to stem cells to encourage them to form islets. If we can find a way to re-supply islet cells to diabetic patients, this may be an effective therapy to stabilise blood sugar levels and reduce the severity of symptoms and morbidity resulting from diabetes, one of the greatest public health concerns of the 21st Century.