Structural studies on SNARE proteins involved in insulin action

糖尿病是一种以高血糖水平为特征的疾病，由胰岛素活性的相对或绝对缺乏引起。胰岛素的降血糖作用是其刺激脂肪和肌肉细胞摄取葡萄糖的能力的结果。詹姆斯教授实验室的一个主要目标是确定参与这种胰岛素调节的葡萄糖摄取的分子。詹姆斯教授已经确定并表征了葡萄糖转运蛋白GLUT4，这是一种通常储存在肌肉和脂肪细胞内的蛋白质。响应于胰岛素刺激，GLUT4移动到细胞表面，在那里它的功能是将葡萄糖转运到细胞中。在过去的5年里，James实验室与其他研究小组合作，发现了几种参与胰岛素调节的细胞内GLUT 4运动的关键蛋白质。我们计划通过获得这些关键蛋白质的高分辨率三维结构来开发这种生物系统的治疗潜力。由此产生的结构信息将使我们能够开发出改变这些关键蛋白质功能的化合物。此类化合物可证明可用作治疗糖尿病的新型治疗剂。本提案的目的是开始实现这一目标。通过将James教授实验室的胰岛素调节葡萄糖转运工作的知识和试剂与Martin博士，Halliday博士和Craik教授实验室的分子和结构生物学专业知识相结合，我们处于实现这一高度重要目标的独特位置。

Diabetes mellitus, a disease characterised by high blood glucose levels, is caused by a relative or absolute deficiency in the activity of insulin. The blood-glucose lowering action of insulin is a result of its ability to stimulate glucose uptake by fat and muscle cells. A major goal of Professor James' laboratory is to identify molecules that are involved in this insulin-regulated uptake of glucose. Professor James has identified and characterised the glucose transporter, GLUT4, a protein that is normally stored inside muscle and fat cells. In response to insulin stimulation, GLUT4 moves to the cell surface where it functions to transport glucose into the cell. Over the past 5 years Professor James laboratory has, in conjunction with other groups, discovered several key proteins that are involved in the insulin-regulated movement of GLUT4 within the cell. We plan to exploit the therapeutic potential of this biological system by obtaining high resolution three dimensional structures of these key proteins. The resulting structural information will allow us to develop compounds that modify the function of these key proteins. Such compounds could prove useful as novel therapeutic agents in the treatment of diabetes. The purpose of this proposal is to begin to implement this goal. By combining the knowledge and reagents coming out of the work on insulin-regulated glucose transport in Professor James' laboratory with the molecular and structural biology expertise in Dr Martin's, Dr Halliday's and Prof Craik's laboratories we are in a unique position to achieve this highly significant goal.