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

该项目的目标是发现新的方法来抑制免疫介导的对1型糖尿病中胰腺β细胞的攻击。利用来自健康和糖尿病临床前研究模型的免疫细胞，该项目将采用药理学方法来测量炎症和细胞毒性分子的产生，以及评估新药如何影响免疫代谢，在这个项目中，候选人将从健康和糖尿病前期患者中分离免疫细胞，临床研究模型和使用药理学方法来测量炎症和细胞毒性分子的产生以及新药如何影响免疫代谢，这是一个新兴的研究领域，对许多疾病过程至关重要。该项目的目标是发现新的方法来抑制免疫介导的对胰腺β细胞的攻击。背景：在1型糖尿病（T1D）中，免疫系统靶向并杀死胰腺β细胞。许多不同免疫细胞的协调作用在β细胞死亡中起作用，包括巨噬细胞和T细胞，它们释放最终导致β细胞死亡的因子。一种新兴的治疗靶点是一种称为AMP活化蛋白激酶（AMPK）的酶。该酶被能量应激激活，一旦激活，激酶通过关闭能量消耗过程（如蛋白质合成和脂肪酸合成）来限制能量消耗，并刺激能量产生途径（如脂肪酸氧化）或通过增强葡萄糖摄取到细胞中。重要的是，AMPK的药理学活化通过增强葡萄糖转运蛋白4（GLUT 4）向质膜的移位来增加葡萄糖摄取到骨骼肌中。这引起了人们对开发用于治疗2型糖尿病的AMPK激活剂的极大兴趣，许多制药公司最近报告了AMPK激活剂在糖尿病模型和2型糖尿病患者中的降糖益处。

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.