Mechanism of pulmonary vascular wall thickening in COVID-19

COVID-19肺血管壁增厚的机制

• 批准号: 10477925
• 负责人: YUICHIRO Justin SUZUKI
• 金额: $ 7.03万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477925
• 关键词: 2019-nCoV; ACE2; Address; Affect; Blood Vessels; COVID-19; COVID-19 mortality; COVID-19 pandemic; COVID-19 patient; Cardiovascular system; Cause of Death; Cells; Development; Elderly; Health; Human; Knowledge; Laboratories; Lung; Mediating; Mitogen-Activated Protein Kinases; Pathogenesis; Pathogenicity; Pathology; Patients; Persons; Predisposition; Pulmonary artery structure; Recombinants; Research; Rest; Role; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Signal Transduction; Smooth Muscle Myocytes; Sociology; Specimen; Testing; Therapeutic Agents; Vascular Smooth Muscle; Viral; Virus; aging population; base; cell growth; combat; comorbidity; influenzavirus; innovation; new therapeutic target; novel; novel therapeutics; pandemic disease; prevent; protein expression; receptor; receptor binding; therapeutic development

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.

总结/摘要 目前，世界正遭受2019年冠状病毒病（COVID-19）的大流行， 严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）， 酶2（ACE 2）作为受体进入宿主细胞。到目前为止，已有超过500万人感染了 SARS-CoV-2和全球超过30万人死于COVID-19，造成严重的健康问题， 经济和社会问题。患有心血管合并症的老年人群 容易受到COVID-19的严重影响并死于COVID-19。然而，这背后的机制 增加的易感性尚未被定义。缺乏这种知识会妨碍 预防COVID-19死亡的治疗策略。我们研究的长期目标是定义 SARS-CoV-2感染的致病机制，以确定新的治疗靶点， 2019冠状病毒病。我们最近发现患者出现肺血管壁增厚 感染SARS-CoV-2死于COVID-19，但未感染SARS-CoV-1或 流感病毒。在这个项目中，我们将测试中心假设，即SARS-CoV-2刺突蛋白 促进肺血管平滑肌细胞中的细胞生长信号传导。这个假设是基于 在我的实验室获得的初步结果表明，（i）用重组SARS-CoV-2治疗， 刺突蛋白（没有其余的病毒成分）强烈地激活细胞生长信号传导（激活 丝裂原活化蛋白激酶）在人肺动脉平滑肌细胞中的表达;（ii）ACE 2 SARS-CoV-2刺突蛋白的受体结合域本身不足以激活细胞生长 （iii）SARS-CoV-2刺突蛋白增加ACE 2的蛋白表达。我们计划 （1）通过以下具体目标实现这一目标： 死于COVID-19的患者的肺血管壁增厚;（2）确定 肺动脉平滑肌细胞中SARS-CoV-2刺突蛋白介导的细胞信号传导;和（3） 定义SARS-CoV-2刺突蛋白介导的细胞信号传导在COVID-19病理学中的作用。这 该项目具有创新性，因为它将解决SARS-CoV-2感染的新机制， 发病机制和肺血管在COVID-19病理学中的作用。本项目的成果 是重要的，因为它们有望有助于开发新的治疗剂， 减少COVID-19造成的死亡，这主要发生在老龄化人口中。