Cerebral vascular pathology of COVID-19

COVID-19 的脑血管病理学

• 批准号: 10553944
• 负责人: Michal Toborek
• 金额: $ 14.84万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553944
• 关键词: 2019-nCoV; ACE2; Acute; Affect; Age; Biological; Blood - brain barrier anatomy; Brain; COVID-19; COVID-19 detection; COVID-19 susceptibility; Cerebrospinal Fluid; Cerebrovascular Disorders; Cerebrovascular system; Cerebrum; Cessation of life; Chronic; Clinical; Coagulation Process; Data; Data Set; Development; Disease; Endothelium; Epigenetic Process; Event; Founder Effect; Future; Genes; Genetic Drift; Health; Hospitalization; Human; Image; Immunity; Infection; Inflammatory; Inflammatory Response; Infusion procedures; Intervention; Investments; Ischemic Stroke; K-18 conjugate; Knowledge; Laboratories; Lead; Left; Long COVID; Morbidity - disease rate; Mus; Neuraxis; Neurologic; Outcome; Pathology; Pathway interactions; Patients; Persons; Pharmacology; Phase; Play; Pneumonia; Population; Proteins; Reaction; Records; Recovery; Reporting; Research; Respirators; Respiratory distress; Role; Route; SARS-CoV-2 infection; SARS-CoV-2 variant; Stroke; Symptoms; Text; The Jackson Laboratory; Therapeutic; Time; Transgenic Mice; Vaccinated; Vaccination; Vaccines; Viral; Virus; Work; Writing; base; brain endothelial cell; cerebral capillary; cerebral microvasculature; cerebrovascular; cerebrovascular pathology; epigenetic regulation; fitness; innovation; microvascular pathology; mortality; mouse model; neurological pathology; neurovascular unit; novel; novel coronavirus; overexpression; prevent; receptor; sex; stroke outcome; transcriptome sequencing; transcriptomics; trend

ABSTRACT COVID-19, which is caused by Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2), has resulted in devastating morbidity and mortality worldwide due to lethal pneumonia and respiratory distress. In addition, the central nervous system (CNS) is well documented to be a target of SARS-CoV-2, and studies detected SARS-CoV-2 in the brain and the cerebrospinal fluid of COVID-19 patients. An increased spread of emerging SARS-CoV-2 variants, such as delta or omicron, appears to be the result of a fitness advantage rather than founder effects and/or genetic drift; therefore, similar trends are expected to continue in the future. While respiratory distress dominates acute clinical symptoms of COVID-19, neurological and cerebrovascular symptoms play a critical role in so called “long-COVID” or chronic COVID. However, the interactions of SARS- CoV-2 with the brain microvasculature and how they predispose to ischemic stroke are largely unknown. The current proposal aims to close this gap of knowledge by its focus on the impact of SARS-CoV-2 on brain microvessels and by focusing on a long-term impact of the infection. The proposal is based on the central hypothesis that SARS-CoV-2 S1 protein affects the integrity of the brain microvessels and affects stroke development via inflammatory responses and epigenetic dysregulation of cerebral microvascular integrity. This hypothesis is novel, and the proposed studies are likely to generate unique data sets. As the result of substantial financial investments, we completed RNA-Seq analyses of transcriptomics signatures of human brain microvascular endothelial cells (HBMEC) infected with SARS-CoV-2. The obtained data allowed us to identify several genes and pathways, which most significantly contribute to SARS-CoV-2-induced cerebral microvascular pathology. The proposal is built on these results. Specifically, we will explore the role of epigenetic regulators in SARS-CoV-2-induced cerebrovascular dysfunction, hyperinflammatory reactions, and ischemic stroke. The impact of SARS-CoV-2 on the cerebral vasculature is largely unknown, making the proposed studies truly innovative. Knowledge of the underlying mechanism(s) of SARS-CoV-2-induced microvascular disruption may provide targets for pharmacological intervention to protect against viral entry into the brain and devastating cerebrovascular pathologies associated with COVID-19 and, especially with a chronic form of this disease. Thus, the outcome of this proposal will provide critically important and therapeutically-relevant information on the involvement of the cerebrovasculature in COVID-19 pathology.

抽象的 COVID-19 是由严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 引起的，已导致 由于致命性肺炎和呼吸窘迫，在全世界范围内造成了毁灭性的发病率和死亡率。此外， 中枢神经系统 (CNS) 已被充分证明是 SARS-CoV-2 的目标，并且研究发现 COVID-19 患者大脑和脑脊液中的 SARS-CoV-2。新兴疾病的传播范围扩大 SARS-CoV-2 变体，例如 delta 或 omicron，似乎是适应性优势的结果，而不是 创始人效应和/或遗传漂变；因此，类似的趋势预计未来仍将持续。尽管 呼吸窘迫在 COVID-19、神经和脑血管急性临床症状中占主导地位 症状在所谓的“长期新冠病毒”或慢性新冠病毒中起着至关重要的作用。然而，SARS 之间的相互作用 CoV-2 与大脑微血管的关系以及它们如何诱发缺血性中风尚不清楚。这 目前的提案旨在通过关注 SARS-CoV-2 对大脑的影响来缩小这一知识差距 微血管并关注感染的长期影响。该提案是根据中央 假设 SARS-CoV-2 S1 蛋白影响脑微血管的完整性并影响中风 通过炎症反应和脑微血管表观遗传失调而发展 正直。这个假设是新颖的，所提出的研究可能会产生独特的数据集。作为 由于大量的财务投资，我们完成了转录组学特征的 RNA-Seq 分析 感染 SARS-CoV-2 的人脑微血管内皮细胞 (HBMEC)。获得的数据允许 我们确定了几个基因和途径，这些基因和途径对 SARS-CoV-2 诱导的脑 微血管病理学。该提案是建立在这些结果的基础上的。具体来说，我们将探讨表观遗传的作用 SARS-CoV-2 诱导的脑血管功能障碍、高炎症反应和缺血性反应的调节因子 中风。 SARS-CoV-2 对脑血管系统的影响在很大程度上尚不清楚，这使得拟议的研究真正 创新的。了解 SARS-CoV-2 诱导的微血管破坏的潜在机制可能 为药物干预提供目标，以防止病毒进入大脑并造成毁灭性的后果 与 COVID-19 相关的脑血管病变，尤其是与该疾病的慢性形式相关的脑血管病变。因此， 该提案的结果将提供极其重要且与治疗相关的信息 脑血管系统参与 COVID-19 病理学。