The Impact of the SARS-CoV-2 Virus on the Integrity of the Blood-brain Barrier

SARS-CoV-2 病毒对血脑屏障完整性的影响

• 批准号: 2034780
• 负责人: Peter Galie
• 金额: $ 29.98万
• 依托单位: Rowan University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2034780&HistoricalAwards=false
• 关键词: Impact; SARS; CoV; Virus; Integrity; Impact; SARS; CoV; Virus; Integrity

The coronavirus disease (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus continues to detrimentally impact the prosperity and welfare of our country. As such, fundamental studies are needed to understand the effects of the virus on the organ systems in the body. In these patients, stroke and delirium are not uncommon. These conditions are associated with breakdown of the blood-brain barrier, which is unique to blood vessels in the central nervous system. The work done with this award will study how the spike protein of the virus affects the blood-brain barrier. Specifically, the junctions between cells lining the inside of blood vessels will be studied. The overall goal is to identify the mechanisms underlying the response to the spike protein. The results of this work may suggest new treatment strategies to mitigate the neurological effects of the SARS-CoV-2 virus. This research will be combined with a program to film instructional on-demand science videos for middle and high school science teachers who are teaching remotely during the COVID-19 pandemic.The hypothesis is that binding of the SARS-CoV-2 spike protein to angiotensin converting enzyme 2 (ACE2) disrupts the blood-brain barrier by inhibiting the protective effect of fluid shear stress mediated by RhoA signaling. Recent studies using samples from human patients have demonstrated that vasculature in the brain expresses ACE2, the primary target for the SARS-CoV-2 virus, but the effects of spike protein-mediated inactivation of ACE2 on the integrity of the blood-brain barrier remain unclear. Here, the studies will use a three-dimensional in vitro model of the blood-brain barrier to interrogate the mechanotransduction mechanisms responsible for the endothelial response to the S1 peptide of the spike protein in the presence of fluid shear stress, accounting for both short-term, cytoskeletal-mediated pathways and long-term, transcriptional changes in the endothelial cells. These studies will elucidate the mechanistic basis for breakdown of the blood-brain barrier in response to coronaviruses such as SARS-CoV-2. The results may explain the increased incidence of stroke and other neuropathologies that occur secondary to the COVID-19 virus.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

严重的急性呼吸综合症2（SARS-COV-2）病毒引起的冠状病毒病（COVID-19）流血继续对我国的繁荣和福利产生不利影响。 因此，需要基本的研究来了解病毒对体内器官系统的影响。在这些患者中，中风和del妄并不少见。 这些疾病与血脑屏障的分解有关，血脑屏障是中枢神经系统中血管独有的。通过该奖项完成的工作将研究病毒的尖峰蛋白如何影响血脑屏障。具体而言，将研究血管内侧的细胞之间的连接。 总体目标是确定对峰值蛋白反应的基础机制。 这项工作的结果可能提出了减轻SARS-COV-2病毒神经系统作用的新治疗策略。这项研究将与一个计划结合，以拍摄中学和高中科学教师的教学课程，这些视频为中学和高中时期的教师进行了远程教学，他们在Covid-19大流行中进行了远程教学。假设是，SARS-COV-2尖峰蛋白与血管紧张素与血管素蛋白与血管紧张素的结合通过障碍物的障碍物来抑制了barro barro，使酶2（ACE2）通过保护性效应来破坏酶的压力。最近使用人类患者样品的研究表明，大脑中的脉管系统表达ACE2，这是SARS-COV-2病毒的主要靶标，但是峰值蛋白介导的ACE2对ACE2的灭活对血脑屏障的完整性的影响仍然不清楚。在这里，研究将使用血脑屏障的三维体外模型来询问导致尖峰蛋白S1肽反应的机械传导机制，这些机制在存在尖峰蛋白的S1肽的情况下考虑了短期，细胞骨架骨骼介导的途径和长期的透视细胞的短期，可转换的细胞。这些研究将阐明响应冠状病毒（例如SARS-COV-2）的血脑屏障的机械基础。 结果可以解释中风和其他神经病理的发病率的增加，而这些奖项反映了NSF的法定任务，并认为使用基金会的知识分子和更广泛的影响审查标准，这反映了NSF的法定任务。