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

项目总结

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.