Novel treatment for respiratory distress due to SARS-CoV2 infection

摘要 新冠肺炎患者的临床后遗症不仅包括急性呼吸窘迫综合征，还包括 通常是急性肾损伤和心力衰竭。这些病理表现为共同的血管内皮细胞激活 潜在的早期损伤反应，内皮细胞表达高水平的血管紧张素转换酶 2(ACE2)，SARS-CoV-2的功能性受体。活化的内皮细胞不仅吸引和促进 白细胞渗入组织，导致细胞因子风暴，导致毛细血管渗漏和水肿。 但也会导致血栓形成。这些机制共同导致组织炎症和缺血，导致 器官衰竭。我们实验室发现，聚合酶三角洲相互作用蛋白2(Poldip2)是一种新的和 是小鼠炎症、内皮通透性和潜在凝血的重要调节剂。老鼠 Poldip2杂合子在很大程度上可以免受脂多糖(LPS)或铜绿假单胞菌诱导的ARDS的影响。 在这里，我们假设Poldip2可能是治疗SARS-CoV-2感染者的新靶点，因为 Poldip2的下调不仅减少了ARDS并发症，如浮肿和细胞因子风暴，而且 也可能潜在地抑制血栓形成。为了验证这一假设，我们建议治疗感染SARS-CoV-2的小鼠 使用一种正在进行临床试验的抗癌药物，我们最近发现该药物可以降低Poldip2水平和 恢复内皮屏障功能。在第一个目标中，我们将使用该试剂下调Poldip2的表达并测试其 SARS-CoV-2感染对血管内皮细胞屏障功能的保护作用及抗炎作用 老鼠。第二个目标将集中在确定抗癌剂的效果和Poldip2的基因消融 基础凝血和SARS-CoV-2感染诱导的凝血。我们预计这种药理作用 Poldip2的下调将代表着一种有希望的新冠肺炎患者的新疗法，这种疗法可以迅速 被转送到诊所。

SUMMARY Clinical sequelae of COVID-19 patients include not only acute respiratory distress syndrome (ARDS), but also often acute kidney injury and heart failure. These pathologies share endothelial activation as a common underlying early response to injury, and endothelial cells express high levels of angiotensin converting enzyme 2 (ACE2), a functional receptor for SARS-CoV-2. Activated endothelium not only attracts and promotes leukocyte infiltration into tissues and contributes to the cytokine storm resulting in capillary leakage and edema, but is also prothrombotic. Together, these mechanisms result in tissue inflammation and ischemia, leading to organ failure. Our laboratory discovered that polymerase delta interacting protein 2 (Poldip2) is a novel and important regulator of inflammation, endothelial permeability and potentially coagulation in mice. Mice heterozygous for Poldip2 are largely protected from lipopolysaccharide (LPS)- or P. aeruginosa-induced ARDS. Here, we hypothesize that Poldip2 may be a novel target for treatment of SARS-CoV-2-infected individuals, as downregulation of Poldip2 not only reduces ARDS complications such as edema and the cytokine storm, but also potentially may inhibit thrombosis. To test this hypothesis, we propose to treat SARS-CoV-2-infected mice with an anti-cancer agent undergoing clinical trials that we have recently shown to reduce Poldip2 levels and restore endothelial barrier function. In the first Aim, we will use this agent to downregulate Poldip2 and test its ability to preserve endothelial barrier function and reduce inflammation in response to SARS-CoV-2 infection in mice. The second aim will focus on determining the effect of the anticancer agent and genetic ablation of Poldip2 on basal coagulation and that induced by SARS-CoV-2 infection. We anticipate that pharmacological downregulation of Poldip2 will represent a promising new treatment for COVID-19 patients that can be rapidly translated to the clinic.