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

由严重急性呼吸系统综合征冠状病毒2 （SARS-CoV-2）病毒引起的冠状病毒病（COVID-19）大流行继续对我国的繁荣和福祉造成不利影响。因此，需要进行基础研究来了解病毒对人体器官系统的影响。在这些患者中，中风和谵妄并不罕见。这些情况与血脑屏障的破坏有关，血脑屏障是中枢神经系统中血管所特有的。获得该奖项的工作将研究病毒的刺突蛋白如何影响血脑屏障。具体来说，将研究血管内部细胞之间的连接。总体目标是确定对刺突蛋白反应的机制。这项工作的结果可能为减轻SARS-CoV-2病毒对神经系统的影响提供新的治疗策略。该研究将与为在新冠肺炎大流行期间远程教学的初中和高中科学教师拍摄教学点播科学视频的计划相结合。假设是SARS-CoV-2刺突蛋白与血管紧张素转换酶2 （ACE2）结合，通过抑制RhoA信号介导的流体剪切应力的保护作用，破坏血脑屏障。最近使用人类患者样本的研究表明，脑血管中表达ACE2，这是SARS-CoV-2病毒的主要靶点，但刺突蛋白介导的ACE2失活对血脑屏障完整性的影响尚不清楚。在这里，研究将使用血脑屏障的三维体外模型来询问在流体剪切应力存在下内皮细胞对刺突蛋白S1肽反应的机械转导机制，考虑内皮细胞短期的细胞骨骼介导途径和长期的转录变化。这些研究将阐明应对SARS-CoV-2等冠状病毒时血脑屏障破裂的机制基础。这一结果可能解释了继发于COVID-19病毒的中风和其他神经病变发病率增加的原因。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.