Tracking metabolic reprogramming through stable isotope-resolved metabolomics

有证据表明，健康细胞和患病细胞消耗和处理营养物质的方式（统称为新陈代谢）是不同的，甚至可以改变它们与邻近细胞沟通、生存和生长的方式。新陈代谢的变化在保护我们免受感染或癌症等危险方面非常重要，但也与神经退行性疾病和代谢紊乱（如肥胖、2型糖尿病和代谢综合征）有关。全身和局部代谢改变也可以影响药物反应和获得抗生素或抗癌药物耐药性。该项目将利用获得和建立一种称为质谱仪的专门设备的优势，该设备能够根据离子在电场和磁场中的运动来确定分析物的质量。通过建立检测方法来测量不同种类的核心代谢物（如氨基酸、碳水化合物、核苷酸、脂质等），本提案的第一个目标是提供在感染、免疫、代谢紊乱和癌症的背景下追踪代谢重新连接的能力，以及它们在不同器官和组织中的全生物体影响。这将有助于深入了解宿主免疫细胞与病原体或癌细胞之间的代谢相互作用，以及这些相互作用最终如何影响疾病结果。本提案的第二个目标是，利用代谢谱来确定对治疗反应的更有效的预测因素，并揭示新的代谢依赖性和脆弱性。这种方法不仅将提供疾病发病机制的新见解，而且还可以使代谢物的生物标志物发现，预测致病过程和对靶向或非靶向治疗的反应。从长远来看，这些知识将有助于确定病原体或肿瘤盔甲的弱点，并最终揭示更有效的治疗策略，其中饮食和代谢目标可以使我们的身体更好地防御“外来”入侵者的攻击。

Evidence suggests that the way cells consume and process nutrients, collectively known as metabolism, differs between healthy and diseased cells and can even change the way they communicate with adjacent cells, survive and grow. Changes in metabolism are very important in protecting us against dangers such as infections or cancer, but have also been implicated in neurodegenerative diseases and metabolic disorders such as obesity, type 2 diabetes, and metabolic syndrome. Both systemic and local metabolic alterations can also affect drug response and the acquisition of antibiotic or anti-cancer drug resistance. This project will draw on the strengths of acquiring and setting up a specialised equipment known as mass spectrometer capable of determining the mass of analytes based on the motion of ions in electric and magnetic fields. Through setting up assays to measure different classes of core metabolites (e.g. amino acids, carbohydrates, nucleotides, lipids etc.) the first objective of this proposal is to provide the capability to track the rewiring of metabolism in the context of infection, immunity, metabolic disorders and cancer, and their organism-wide implications across different organs and tissues. This will assist with gaining insight into the metabolic interplay between host immune cells and pathogens or cancer cells and how these interactions ultimately affect disease outcomes. The second objective of this proposal is, to exploit metabolic profiles to identify more effective predictors of response to therapy and unveil novel metabolic dependencies and vulnerabilities. This approach will not only provide novel mechanistic insights of disease pathogenesis, but could also enable biomarker discovery of metabolites that predict pathogenic processes and the response to targeted or untargeted therapies. In the longer term this knowledge will help identify weaknesses in the pathogen or the tumour's armour and ultimately unveil more effective therapeutic strategies where diet and metabolic targets could empower our body to better defend attacks by "foreign" invaders.