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

项目摘要 2019年冠状病毒病（又称COVID-19）造成了前所未有的全球健康危机。 到目前为止，最大限度地减少病毒传播的唯一策略是物理距离。可惜这些 这些努力正在对国家的精神健康产生负面影响，并破坏我们的经济。因此 必须尽快开发出COVID-19的治疗方法。 蠕虫（秀丽隐杆线虫）和斑马鱼（斑马鱼）是具有以下特征的首要模式生物： 从历史上看，它为许多人类疾病提供了深刻的见解。然而，此时，应用程序 蠕虫和斑马鱼对COVID-19的反应非常有限。目前的主要问题是， 报告了这些动物的模型，以捕捉COVID-19的复杂病理生理学。总体 本提案的目的是建立一种资源，帮助弥补这一差距。具体而言，我们的目标是 促进代谢组学应用于蠕虫和斑马鱼的COVID-19相关研究。 我们工作的基础将是对COVID-19人类患者的代谢组学分析。除了 比较患有轻度和重度疾病的患者，来自感染患者的样本将与 从同一个病人身上提取样本。总之，我们希望这些实验能提供一个 全面了解COVID-19病理过程中改变的代谢途径。 然后，我们将把我们在患者中发现的代谢功能障碍映射到蠕虫和斑马鱼的代谢组中 通过使用我们在家长奖中开发的技术。结果将是一个资源， 蠕虫和斑马鱼中COVID-19参考途径的综合集合。这将授权使用 蠕虫和斑马鱼来回答重要的COVID-19问题，其中两个例子我们建议继续研究 这里.我们的第一个问题是：临床试验中的小分子药物治疗COVID的作用模式是什么- 19例患者（例如，羟氯喹）？我们将对暴露于以下物质的斑马鱼进行剂量反应代谢组学研究： 目前正在临床试验中的20种小分子药物用于治疗COVID-19。每种药物的靶点与 参考COVID-19途径将提供对作用模式、脱靶毒性的深入了解，并可能有助于 在改进新药的设计上。我们的第二个问题是：哪些疾病过程导致了COVID-19 19病理学？我们将在细胞因子风暴、呼吸窘迫和 器官衰竭将这些模型的代谢变化与参考COVID-19途径进行比较， 提高我们对哪些疾病过程导致COVID-19病理学的理解。 我们注意到，我们在这里建议评估的药物和疾病过程在很大程度上是不完整的， 与许多其他药物和C. elegans疾病模型可供测试。这些机会，以及许多 其他，代表了我们的资源在未来的令人兴奋的应用，以促进我们对COVID-19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.