Skeletal muscle and adipose cross talk identifying novel mediators of insulin sensitivity

候选脂肪/肌肉串扰介质在调节人体组织中的细胞代谢和胰岛素信号活动方面的作用尚未得到很好的证实。为了确定关键的串扰介质，并验证它们在调节细胞代谢和胰岛素信号通路中的作用，关键是最初使用人源性原代细胞进行此类研究，然后将这些发现反向翻译成适当的体内模型。本研究的目的是研究肌肉/脂肪细胞串扰的作用及其对骨骼肌代谢表型和胰岛素信号的影响，以便在临床前模型中识别和验证介导胰岛素敏感性和细胞代谢的新靶点。机械性脂肪和肌肉细胞的串扰研究主要是使用小鼠细胞(如C2C12细胞)进行的，由于它们的代谢表型不同，不适合进行靶标识别研究。重要的是，对于这项研究，我们收集了大量且不断增长的人体肌肉和患者匹配的脂肪样本，这些样本来自瘦人和肥胖者。此外，将使用原代人类肌管和患者匹配的脂肪细胞进行体外细胞串扰研究。然后，我们将把这些发现反向翻译成适当的动物模型，以便进行体内靶标验证研究。因此，该项目的目标如下。1.通过对正常体重和肥胖者的脂肪组织和蛋白质组质谱学分析，确定新的脂肪/肌肉串扰介质2.建立定制的人体脂肪/肌肉串扰体外模型3.利用合适的模型验证新的脂肪/肌肉串扰介体调节细胞代谢表型和胰岛素敏感性的作用

The role of candidate adipose/muscle cross-talk mediators in mediating cellular metabolism and insulin signalling activity in human tissues is not well established. In order to identify the key cross-talk mediators and to validate their role in regulating cellular metabolism and insulin signalling pathways it is critical to initially conduct such studies using human derived primary cells, and then to back-translate these findings into appropriate in vivo models. The objective of this studentship is to investigate the role of muscle/adipose cellular cross talk and its effect of skeletal muscle metabolic phenotype and insulin signalling so that new targets which mediate insulin sensitivity and cellular metabolism can be identified and validated in preclinical models. Mechanistic adipose and muscle cellular cross-talk studies have predominantly been performed using murine cells (e.g C2C12 cell line), which are not suitable for target identification studies due to their different metabolic phenotype. Importantly, for this study we have a substantial and growing collection of human muscle and patient-matched adipose samples from both lean and obese individuals. Furthermore, in vitro cellular cross-talk studies will be conducted using primary human myotubes and patient-matched adipocytes. We will then back-translate these findings into appropriate animal models in order to perform in vivo target validation studies. The objectives of this project are therefore as follows. 1. To identify novel adipose/muscle cross-talk mediators through lipidomic and proteomic mass-spectroscopy analysis of human adipose tissue from both normal weight and obese individuals 2. Establish bespoke ex vivo models of human adipose/muscle cross-talk 3. Validate using appropriate models novel mediators of adipose/muscle cross-talk in regulating cellular metabolic phenotype and insulin sensitivity