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不足引起。胰岛素的降血糖作用是由于它能够刺激脂肪和肌肉细胞摄取葡萄糖。詹姆斯教授实验室的一个主要目标是确定参与胰岛素调节的葡萄糖摄取的分子。詹姆斯教授已经确定了葡萄糖转运蛋白GLUT4的特征，这是一种通常储存在肌肉和脂肪细胞中的蛋白质。作为对胰岛素刺激的反应，GLUT4移动到细胞表面，在那里它起到将葡萄糖输送到细胞内的作用。在过去的5年里，詹姆斯教授实验室与其他团队合作，发现了几种关键蛋白质，这些蛋白质参与了细胞内GLUT4的胰岛素调节运动。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个生物系统的治疗潜力。由此得到的结构信息将使我们能够开发出修改这些关键蛋白质功能的化合物。这些化合物可能会被证明是治疗糖尿病的新型治疗剂。这项建议的目的是开始实施这一目标。通过将詹姆斯教授实验室在胰岛素调节葡萄糖运输方面的知识和试剂与马丁博士、哈利迪博士和克雷克教授实验室的分子和结构生物学专业知识相结合，我们处于独特的地位，能够实现这一极其重要的目标。

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.