Ligand bias at the GLP-1 receptor as a means of favouring cytoprotection

细胞死亡发生在许多疾病中，如2型糖尿病，帕金森病和阿尔茨海默病，预防这种情况（“细胞保护”）可能是一种有用的治疗方法。一种名为GLP-1的天然激素可以保护细胞，但由于恶心，不能使用高剂量。最近已经表明，与GLP-1类似的其他分子在触发细胞保护方面往往比其他分子更好。在这个项目中，我将测试这些GLP-1样分子的保护作用。为此，我将测量这些分子在试管中保护细胞免受高糖/高脂肪混合物的能力，就像在糖尿病患者的血液中发现的那样。利用对每个分子组成的了解，我将确定有利的特征，并将这些特征联合收割机结合起来，以找到比目前可用的分子更好的分子。然后，我将测试细胞保护作用的差异是否是由于它们对细胞内一种称为β-抑制蛋白的分子的影响。最后，我将研究最有希望的分子是否可以在活的生物体中起作用，将它们给予小鼠，看看这是否可以保护胰岛素产生细胞免受一种叫做链脲佐菌素的毒药的影响。如果这些实验成功，最有希望的分子可以开发成药物，帮助患有2型糖尿病和其他疾病的人。

Cell death occurs in many diseases such as type 2 diabetes, Parkinsons disease and Alzheimers disease, and preventing this ("cytoprotection") might be a useful treatment. A natural hormone called GLP-1 protects cells, but high doses cannot be used because of nausea. It has recently been shown that other molecules similar to GLP-1 tend to be better than others at triggering cytoprotection. In this project I will test a collection of these GLP-1-like molecules for their protective effect.To do this, I will measure the ability of these molecules to protect cells in a test tube from a high sugar / high fat mix, as is found in the blood of people with diabetes. Using knowledge of the components of each molecule I will identify advantageous features and combine these to find a molecule which is better than those currently available. I will then test whether the difference in cytoprotection is due to their effect on a molecule inside cells called beta-arrestin. Finally, I will investigate whether the most promising molecules can work in living organisms by giving them to mice and seeing if this protects insulin-producing cells from a poison called streptozotocin. If these experiments are successful, the most promising molecules could be developed into drugs to help people with type 2 diabetes and other diseases.