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

点击翻译按钮获取中文摘要

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.