Pharmacological targeting of AMP-activated protein kinase for immune cell regulation in Type 1 Diabetes

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The ambition of this project is to discover new approaches to dampen the immune-mediated attack on the pancreatic beta cell seen in type-1 diabetes. Using immune cells from healthy and diabetic pre-clinical research models, this project will employ pharmacological approaches to measure production of inflammatory and cytotoxic molecules as well as assessment of how novel drugs affect immunometabolism, an emerging area of research fundamental to many disease processes.In this project the candidate will isolate immune cells from healthy and diabetic pre-clinical research models and use pharmacological approaches to measure production of inflammatory and cytotoxic molecules as well as how novel drugs affect immunometabolism, an emerging area of research that is fundamental to many disease processes. The ambition of this project is to discover new approaches to dampen the immune-mediated attack on the pancreatic beta cell.Background: In Type 1 Diabetes (T1D), the immune system targets and kills pancreatic beta cells. The coordinated action of a number of different immune cells play a role in beta cell death including macrophages and T cells, which release factors that ultimately lead to beta cell death. One emerging therapeutic target is an enzyme called AMP-activated protein kinase (AMPK). The enzyme is activated by energy stress and once active, the kinase limits energy consumption by switching off energy consuming processes such as protein synthesis and fatty acid synthesis and stimulates energy-producing pathways such as fatty acid oxidation or by enhancing glucose uptake into the cell. Importantly pharmacological activation of AMPK increases glucose uptake into skeletal muscle, by enhancing glucose transporter 4 (GLUT4) translocation to the plasma membrane. This has led to significant interest in developing AMPK activators for treatment of Type 2 diabetes, with a number of drug companies recently reporting glucose-lowering benefits of AMPK activators in models of diabetes and in people with type 2 diabetes.