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

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.

由严重急性呼吸道综合征冠状病毒2型（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产生不利影响。 因此，需要进行基础研究，以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。 这些病症与血脑屏障的破坏有关，血脑屏障是中枢神经系统血管所特有的。该奖项所做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的反应的机制。 这项工作的结果可能会提出新的治疗策略，以减轻SARS-CoV-2病毒的神经影响。这项研究将与一个项目相结合，为在COVID-19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。该假设是SARS-CoV-2刺突蛋白与血管紧张素转换酶2（ACE 2）的结合通过抑制RhoA信号传导介导的流体剪切应力的保护作用来破坏血脑屏障。最近使用人类患者样本的研究表明，脑中的血管系统表达ACE 2，这是SARS-CoV-2病毒的主要靶点，但刺突蛋白介导的ACE 2失活对血脑屏障完整性的影响仍不清楚。在这里，研究将使用血脑屏障的三维体外模型来询问机械转导机制，该机制负责在流体剪切应力的存在下对刺突蛋白的S1肽的内皮反应，解释短期的细胞内介导的途径和长期的内皮细胞的转录变化。这些研究将阐明血脑屏障对冠状病毒（如SARS-CoV-2）的反应机制。 该研究结果可以解释中风和其他继发于COVID-19病毒的神经病变发病率增加的原因。该奖项反映了NSF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。

项目成果

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier.

• DOI: 10.1016/j.nbd.2020.105131
• 发表时间: 2020-12
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Buzhdygan TP;DeOre BJ;Baldwin-Leclair A;Bullock TA;McGary HM;Khan JA;Razmpour R;Hale JF;Galie PA;Potula R;Andrews AM;Ramirez SH
• 通讯作者: Ramirez SH

Oxygen gradients dictate angiogenesis but not barriergenesis in a 3D brain microvascular model

• DOI: 10.1002/jcp.30840
• 发表时间: 2022-07-28
• 期刊: JOURNAL OF CELLULAR PHYSIOLOGY
• 影响因子: 5.6
• 作者: Tran，Kiet A.;Baldwin-Leclair，Abigail;Galie，Peter A.
• 通讯作者: Galie，Peter A.