Mechanism of pulmonary vascular wall thickening in COVID-19

摘要/摘要 目前，世界正在遭受2019年冠状病毒病(新冠肺炎)的大流行，引起 使用血管紧张素转换的SARS冠状病毒2(SARS-CoV-2) 酶2(ACE2)作为受体进入宿主细胞。到目前为止，已有500多万人感染了 全球已有30多万人死于新冠肺炎，造成严重健康问题， 经济和社会学问题。患有心血管合并症的老龄化人口非常多 容易受到新冠肺炎的严重影响并死于微博。然而，这背后的机制 增加的敏感度还没有定义。缺乏这样的知识干扰了 新冠肺炎预防死亡的治疗策略。我们研究的长期目标是确定 SARS-CoV-2感染的致病机制寻找新的治疗靶点 新冠肺炎。我们最近发现患者发生了肺血管壁增厚。 感染SARS-CoV-2而死于新冠肺炎的患者，但不是感染SARS-CoV-1或 流感病毒。在这个项目中，我们将检验SARS-CoV-2刺突蛋白的中心假设 促进肺血管平滑肌细胞中的细胞生长信号。这一假设是基于 我实验室获得的初步结果表明：(一)重组SARS-CoV-2治疗 Spike蛋白(不含其余病毒成分)强烈激活细胞生长信号(激活 (Ii)血管紧张素转换酶2 SARS-CoV-2刺突蛋白受体结合区单独不足以激活细胞生长 SARS-CoV-2刺突蛋白上调ACE2的蛋白表达。我们计划 通过解决以下具体目标来实现目标：(1)建立统一的 新冠肺炎死亡患者肺血管壁增厚；(2)探讨心绞痛发病机制 SARS-CoV-2刺突蛋白介导的肺动脉平滑肌细胞信号转导； 明确SARS-CoV-2刺突蛋白介导的细胞信号在新冠肺炎病理中的作用。这 该项目具有创新性，因为它将解决SARS-CoV-2感染的新机制，并 肺血管在新冠肺炎发病机制中的作用。本项目的成果 具有重要意义，因为它们有望为开发新的治疗药物做出贡献 减少新冠肺炎导致的死亡，这主要发生在老龄化人口中。

Summary/Abstract Currently the world is suffering from the pandemics of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter host cells. So far, over five million people have been infected with SARS-CoV-2 and over 300,000 people have died of COVID-19 worldwide, causing serious health, economical, and sociological problems. The aging population with cardiovascular comorbidities is highly susceptible to be severely affected by and die of COVID-19. However, the mechanism underlying this increased susceptibility has not been defined. Lack of such knowledge interferes with the development of therapeutic strategies to prevent death by COVID-19. The long-term objective of our research is to define the pathogenic mechanism of the SARS-CoV-2 infection to identify new therapeutic targets to combat COVID-19. We recently identified the occurrence of pulmonary vascular wall thickening in patients infected with SARS-CoV-2 who died of COVID-19, but not in patients infected with SARS-CoV-1 or influenza virus. In this project, we will test the central hypothesis that the SARS-CoV-2 spike protein promotes cell growth signaling in lung vascular smooth muscle cells. This hypothesis is based on preliminary results obtained in my laboratory showing that (i) the treatment with recombinant SARS-CoV-2 spike protein (without the rest of viral components) strongly activates cell growth signaling (the activation of mitogen-activated protein kinase) in human pulmonary artery smooth muscle cells; (ii) the ACE2 receptor binding domain of SARS-CoV-2 spike protein alone is not sufficient to activate cell growth signaling; and (iii) SARS-CoV-2 spike protein increases the protein expression of ACE2. We plan to accomplish the objective by addressing the following specific aims: (1) Establish the uniformity of pulmonary vascular wall thickening in patients who died of COVID-19; (2) Determine the mechanism of SARS-CoV-2 spike protein-mediated cell signaling in pulmonary artery smooth muscle cells; and (3) Define the role of SARS-CoV-2 spike protein-mediated cell signaling in the COVID-19 pathology. This project is innovative because it will address a novel mechanism of the SARS-CoV-2 infection and pathogenesis and the role of pulmonary vasculatures in the pathology of COVID-19. Results of this project are significant because they are expected to contribute to the development of new therapeutic agents to reduce the death caused by COVID-19 that occurs largely in the aging population.