Novel treatment for respiratory distress due to SARS-CoV2 infection

总结 COVID-19患者的临床后遗症不仅包括急性呼吸窘迫综合征（ARDS）， 通常是急性肾损伤和心力衰竭。这些病理共有内皮活化作为共同的 潜在的早期反应损伤，和内皮细胞表达高水平的血管紧张素转换酶 2（ACE 2），SARS-CoV-2的功能性受体。激活的内皮细胞不仅吸引和促进 白细胞浸润到组织中并促成细胞因子风暴导致毛细血管渗漏和水肿， 但也是促血栓形成的。这些机制共同导致组织炎症和缺血， 器官衰竭我们的实验室发现，聚合酶δ相互作用蛋白2（Poldip 2）是一种新的， 小鼠中炎症、内皮渗透性和潜在凝血的重要调节剂。小鼠 Poldip 2杂合的人在很大程度上受到保护，免受脂多糖（LPS）或铜绿假单胞菌诱导的ARDS。 在此，我们假设Poldip 2可能是治疗SARS-CoV-2感染个体的新靶点， Poldip 2的下调不仅减少了ARDS并发症如水肿和细胞因子风暴， 也可能抑制血栓形成。为了验证这一假设，我们建议治疗SARS-CoV-2感染的小鼠， 一种正在进行临床试验的抗癌药物，我们最近发现它可以降低Poldip 2水平， 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Poldip 2并测试其在细胞中的表达。 在SARS-CoV-2感染后保持内皮屏障功能并减少炎症的能力 小鼠第二个目标将集中于确定抗癌剂和Poldip 2基因消融的效果。 对基础凝血功能和SARS-CoV-2感染诱导的凝血功能的影响。我们预计， Poldip 2的下调将代表一种有希望的新型COVID-19患者治疗方法， 翻译到诊所

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.