A COMPREHENSIVE RESOURCE FOR HIGH-THROUGHPUT PROFILING OF WORM AND ZEBRAFISH METABOLOMES

项目摘要 冠状病毒病2019年，也被称为新冠肺炎，造成了一场前所未有的全球健康危机。 到目前为止，将病毒传播降至最低的唯一策略是物理距离。不幸的是，这些 这些努力正在对国家的精神健康产生负面影响，并摧毁我们的经济。因此，它是 迫切需要尽快开发出治疗新冠肺炎的方法。 蠕虫(秀丽线虫)和斑马鱼(Danio Rerio)是具有 历史上提供了对许多人类疾病的深刻洞察。然而，此时，应用程序 蠕虫和斑马鱼进入新冠肺炎的数量受到了严格限制。目前的主要问题是，没有 报道了这些动物的模型，以捕捉新冠肺炎的复杂病理生理。最重要的是 当前提案的目标是创建一种资源，帮助弥合这一差距。具体来说，我们的目标是 促进代谢组学在蠕虫和斑马鱼新冠肺炎相关研究中的应用。 我们工作的基础将是对人类新冠肺炎患者的代谢分析。除了……之外 比较轻度和重度疾病的患者，来自感染患者的样本将与 康复后取自同一病人的样本。总而言之，我们希望这些实验能够提供一个 新冠肺炎病理过程中改变的代谢途径的综合图片。 然后，我们将把我们在患者身上发现的代谢功能障碍映射到蠕虫和斑马鱼的代谢物上 通过使用我们在母公司奖项中开发的技术。结果将是一个资源，它描述了 蠕虫和斑马鱼中新冠肺炎途径的全面参考集。这将使使用 蠕虫和斑马鱼回答重要的新冠肺炎问题，这是我们建议探讨的两个例子 这里。我们的第一个问题是：小分子药物在治疗COVID的临床试验中的作用模式是什么？ 19例患者(如羟基氯喹)？我们将对染毒的斑马鱼进行剂量反应代谢组学研究 目前正在进行临床试验的20种治疗新冠肺炎的小分子药物。每种药物的靶点与 参考新冠肺炎途径将提供对作用模式、靶外毒性的洞察，并可能提供帮助 在新药的改进设计中。我们的第二个问题是：哪些疾病过程对COVID有贡献- 19病理学？我们将对斑马鱼细胞因子风暴、呼吸窘迫和 器官衰竭。将这些模型中的代谢变化与参考新冠肺炎途径进行比较将 提高我们对哪些疾病过程有助于新冠肺炎病理的理解。 我们注意到，我们在这里建议评估的药物和疾病过程基本上是不完整的， 有许多额外的药物和线虫疾病模型可供测试。这些机会，以及许多 其他的，代表着令人兴奋的未来应用我们的资源，以增进我们对新冠肺炎的理解 通过使用模型动物。

Project Summary Coronavirus disease 2019, also known as COVID-19, has created an unprecedented global health crisis. Thus far, the only strategy to minimize spread of the virus has been physical distancing. Unfortunately, these efforts are negatively impacting the psychiatric health of the nation and devastating our economy. It is therefore imperative that a treatment for COVID-19 be developed expeditiously. Worms (Caenorhabditis elegans) and zebrafish (Danio rerio) are premier model organisms that have historically provided profound insight into a number of human diseases. At this time, however, the application of worms and zebrafish to COVID-19 has been severely limited. Currently, the major issue is that there are no reported models in these animals to capture the complex pathophysiology of COVID-19. The overarching objective of the current proposal is to create a resource that will help bridge this gap. Specifically, we aim to facilitate the application of metabolomics to COVID-19 related studies in worms and zebrafish. The basis of our work will be metabolomic analysis of human patients with COVID-19. In addition to comparing patients with mild and severe disease, samples from an infected patient will be compared to samples from the same patient after recovery. Together, we expect these experiments to provide a comprehensive picture of metabolic pathways that are altered during COVID-19 pathology. We will then map the metabolic dysfunction we uncover in patients to the worm and zebrafish metabolomes by using technologies that we have developed in the parent award. The result will be a resource delineating a comprehensive set of reference COVID-19 pathways in worms and in zebrafish. This will empower the use of worms and zebrafish to answer important COVID-19 questions, two examples of which we propose to pursue here. Our first question is: what is the mode of action of small-molecule drugs in clinical trials to treat COVID- 19 patients (e.g., hydroxychloroquine)? We will perform dose-response metabolomics on zebrafish exposed to 20 small-molecule drugs currently in clinical trials to treat COVID-19. A comparison of each drug’s target to reference COVID-19 pathways will provide insight into mode of action, off-target toxicity, and potentially assist in the improved design of new drugs. Our second question is: which disease processes contribute to COVID- 19 pathology? We will perform metabolomics on zebrafish models of cytokine storm, respiratory distress, and organ failure. Comparing metabolic changes from each of these models to reference COVID-19 pathways will improve our understanding of which disease processes contribute to COVID-19 pathology. We note that the drugs and disease processes that we propose to evaluate here are largely incomplete, with many additional drugs and C. elegans disease models available to test. These opportunities, and many others, represent exciting future applications of our resource to advance our understanding of COVID-19 through the use of model animals.