Metabolomic approaches to identify pathophysiological biomarkers of stroke

学生奖学金战略优先领域：基础与临床研究关键词：中风，代谢组学，转录组学，生物标志物，药理学生物标志物全球中风是仅次于冠状动脉疾病的死亡原因，每年造成600多万人死亡。这种疾病是由于血液流向大脑被阻塞而引起的，无论是由于缺血性中风（其中血液流动在某些血管中被阻塞）还是出血性中风，其中血管出血。在任何一种情况下，由受损血管供血的大脑部分都会停止运作。短暂性脑缺血发作是缺血性中风的一种形式，但在几小时或更短时间内自行消退，因此造成的损害较小。治疗中风的选择是罕见的。缺氧是一个关键的因果关系，但与中风相关的其他生化变化也会造成损害。这些包括代谢途径的变化，如多胺途径和炎症增加，通过犬尿氨酸途径等途径表现出来。我们以前的工作已经显示了这些途径的变化，以及发现了一种新的代谢物，与与中风相关的三甲胺N-氧化物有关。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学的贡献，以及最终是否可以通过新化合物来靶向它们，这些新化合物可以被开发用于中风管理的新疗法。评估中风或短暂性脑缺血发作患者的代谢组学数据集，以寻找与病情相关的途径和代谢物2。探索公开可用的转录组数据库，以确定基因转录变化是否与代谢变化相关。为了探测，使用质谱，结构的三甲基胺N-氧化物（TMO）衍生的代谢产物，我们发现与中风4。启动研究卒中相关代谢途径的药理学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