Metabolomic approaches to identify pathophysiological biomarkers of stroke

学生战略优先领域：基础和临床研究关键词：中风，代谢组学，转录学，生物标记物，药物抑制物全球中风是仅次于冠状动脉疾病的死亡原因，每年导致600多万人死亡。由于缺血性中风(某些血管的血液流动受阻)或出血性中风(血管出血)导致大脑血流受阻，这种疾病就会发生。在任何一种情况下，大脑中由受损血管供血的部分都会停止功能。短暂性脑缺血发作是一种缺血性中风，但会在几个小时或更短的时间内自行解决，因此造成的损害较小。管理中风的治疗选择很少。缺氧是一个关键的原因，但与中风相关的其他生化变化也是造成损害的原因。这些变化包括代谢途径的改变，如多胺途径和炎症增加，通过诸如犬尿氨酸途径等途径表现出来。我们之前的工作显示了这些通路的变化，以及发现了一种新的代谢物，与三甲胺N-氧化物有关，与中风有关。该项目旨在更多地了解这些变化的性质，这些代谢物对中风相关病理的贡献，以及最终它们是否可能成为新的化合物的靶点，从而可以开发出新的中风治疗方法。目的：1.评估中风或短暂性脑缺血发作患者的代谢组学数据，以寻找与条件相关的途径和代谢物。探索公开可用的转录数据库，以确定基因转录变化是否与已识别的代谢变化相关。为了用质谱学探测我们发现与中风4相关的三甲胺N氧化物(TMO)衍生代谢物的结构。开展研究与中风相关的代谢途径的药理抑制剂在预防疾病中的潜在用途的工作

Studentship strategic priority area:Basic & Clinical ResearchKeywords: Stroke, Metabolomics, transcriptomics, biomarkers, pharmacological inhibitorsGlobally Stroke is second only to coronary artery disease as a cause of death, killing over 6 million people each year. The disease arises as blood flow is occluded to the brain, either due to ischemic stroke (where blood flow is blocked in certain vessels) or hemorrhagic stroke, where vessels bleed. In either case, the part of the brain fed by the damaged vessels ceases to function. Transient ischemic attacks are a form of ischemic stroke but which self-resolve within a few hours or less, thus causing less damage. Therapeutic options to manage stroke are rare. Lack of oxygen is a critical causal effect, but other biochemical changes associated with stroke contribute to damage. These include changes to metabolic pathways, such as the polyamine pathway and increased inflammation, manifesting through pathways such as the kynurenine pathway. Our previous work has shown changes to these pathways as well as the discovery of a novel metabolite, related to trimethylamine N-oxide that are associated with stroke. This project aims to learn more about the nature of these changes, the contribution these metabolites make to stroke related pathology and ultimately whether they may be targeted by new compounds that can be developed towards new therapies for stroke management.Aims:1. To evaluate metabolomics datasets from individuals having suffered a stroke or transient ischemic attack to seek pathways and metabolites associated with the condition2. To probe publicly available transcriptomic databases to determine whether gene transcript changes associate with the metabolic changes identified3. To probe, using mass spectrometry, the structure of a trimethylamine N-oxide (TMO) derived metabolite we have found to be associated with stroke4. To initiate work investigating the potential use of pharmacological inhibitors of metabolic pathways associated with stroke in protecting against the disease