Regulation of inflammatory gene expression during SARS2 infection

项目总结 感染引起炎症，这有助于病原体清除和宿主的生存 有机体。然而，未能调节炎症反应往往会导致多个器官 对宿主的损害和致命性。在目前的新冠肺炎大流行中引起的严重急性 呼吸综合征冠状病毒2(SARS-CoV-2)，细胞因子水平升高的患者有 通常与严重的症状和死亡率有关。这表明特定的 炎症分子可能是导致死亡和发病率的一个因素，与 病毒本身。因此，迫切需要更好地了解基因的激活动力学。 感染，并开发治疗方法来管理炎症反应。在2016年，我们展示了 控制炎症基因染色质重塑的因素的表观遗传抑制，如 拓扑异构酶1，可减少炎症基因的表达，挽救细菌的致死性 和病毒感染，提示这些作用可能适用于新冠肺炎的设置为 井。拓扑异构酶1抑制剂是FDA批准的，并在世卫组织基本药物清单中， 因此，如果他们积极对抗新冠肺炎，他们的广泛使用和低廉的成本可以被利用 就像他们在许多其他感染中一样。在本提案中，我们将描述Top1和Top1的角色 SARS-CoV-2感染过程中控制染色质拓扑的表观遗传因素 TOP1抑制剂作为药物治疗新冠肺炎动物模型的可行性。我们 将使用表观遗传抑制剂进行机制和临床前测试 临床试验中使用的免疫阻滞剂和目前的护理标准(糖皮质激素)。

PROJECT SUMMARY Infection causes inflammation, which contributes to pathogen clearance and survival of the host organism. However, failure to regulate the inflammatory response can often lead to multiple organ damage and lethality for the host. In the current COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with elevated cytokine levels are often associated with severe symptoms and mortality. This indicates hyper-activation of specific inflammatory molecules might be as much a contributing factor to mortality and morbidity as the virus itself. Thus, there is a dire need to better understand the gene activation dynamics upon infection and develop therapies to manage the inflammatory response. In 2016 we have shown that epigenetic inhibition of factors controlling chromatin remodeling of inflammatory genes, like Topoisomerase 1, can reduce inflammatory gene expression and rescue lethality during bacterial and viral infection, suggesting that these effects may be applicable in the setting of COVID-19 as well. Topoisomerase 1 inhibitors are FDA approved and in the list of WHO essential medicines, thus their widespread usage and cheap cost can be leverage if they are active against COVID-19 as they are in many other infections. In this proposal, we will characterize the role of Top1 and epigenetic factors controlling chromatin topology during SARS-CoV-2 infection and will test the feasibility of use of Top1 inhibitors as drugs for the treatment of COVID-19 in animal models. We will perform mechanistic and preclinical test using epigenetic inhibitors in comparison with immune blockers used in clinical trials and the current standard of care (glucocorticoids).