Neurogenin 3: regulation of protein stability.

糖尿病是由于产生胰岛素的细胞，称为胰岛细胞的丧失或不活动引起的。我们可以治疗糖尿病的方法之一是用干细胞取代这些细胞，这些干细胞已经被指示变成胰岛。神经原蛋白3(NGN3)是一种推动胰岛形成的蛋白质，其中NGN3蛋白的含量是非常重要的。我们发现NGN3蛋白是不稳定的，并在体内的细胞中迅速被破坏。这项提案旨在研究控制这种破坏的方式。当我们理解了这一点，我们就可以制造出能够抵抗分解的改变形式的NGN3。在这些初步研究中，我们将把这些稳定形式的NGN3注射到蝌蚪体内，看看它们是否真的存在于更高水平，因此比原始蛋白质更活跃。蝌蚪是这项研究的绝佳选择，因为它们很大，在母体外发育，很容易注入蛋白质。此外，我们已经知道蝌蚪对正常的NGN3做出反应，因此可以作为一个有用的系统来测试NGN3活性的增加。然后我们将看看我们改变的NGN3在培养的哺乳动物细胞中是否也是稳定的。这些研究将为实验铺平道路，看看稳定的NGN3是否可以被重新加入干细胞，以鼓励它们形成胰岛。如果我们能找到一种方法为糖尿病患者重新供应胰岛细胞，这可能是一种稳定血糖水平、降低糖尿病引起的症状和发病率的有效疗法，糖尿病是21世纪最大的公共卫生问题之一。

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.