Brain pathophysiology in SARS-CoV-2 disease

SARS-CoV-2 疾病的脑病理生理学

基本信息

批准号：
10317394
负责人：
JUAN M SAAVEDRA
金额：
$ 66.15万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10317394
关键词：
2019-nCoV ACE2 Affect Age Ageusia Aging Angiotensin II Type 1 Receptor Blockers Angiotensins Animal Model Anosmia Anxiety Arm Injuries Attenuated Autopsy Behavior Binding Blood - brain barrier anatomy Blood Coagulation Factor Blood Vessels Blood coagulation Brain Brain Injuries Brain Pathology COVID-19 COVID-19 pandemic COVID-19 patient COVID-19 severity Cells Cerebral hemisphere hemorrhage Cerebrovascular Disorders Cerebrum Clinical Trials Coagulation Process Cognition Cognitive Complement Activation Confusion Disease Endothelial Cells Endothelium Enzymes Exhibits Experimental Models Fibrin Functional disorder Future Gram-Negative Bacteria Hamsters Headache Hippocampus (Brain)Hormonal Hormones Impairment Infiltration Inflammation Inflammatory Injury Interleukin-1 beta Interleukin-6 Ischemic Stroke Knockout Mice Lesion Light Lipopolysaccharides Lung Membrane Microglia Modeling Mus NF-kappa B Neuraxis Neurologic Symptoms Neurons Pathology Pathway interactions Peripheral Pharmacologic Substance Platelet Activation Play Production Proteins Prothrombin Receptor, Angiotensin, Type 1 Renin-Angiotensin System Reporting Research Risk Factors Role SARS-CoV-2 infection Signal Pathway Signal Transduction Symptoms TLR2 gene TLR4 gene Testing Therapeutic Clinical Trial Thrombin Thrombosis Tissues Vasoconstrictor Agents Venous Thrombosis Viral Virus arm behavioral impairment biological adaptation to stress biological sex brain endothelial cell brain parenchyma cerebral capillary cerebral microvasculature cerebrovascular cytokine endothelial dysfunction experimental study immunothrombosis insight male member neuroinflammation neuron loss overexpression sex thrombotic

项目摘要

SARS-CoV-2, the virus underlying the current COVID-19 pandemic, not only affects peripheral tissues, it also targets the brain causing microvascular lesions, microhemorrhages and neurological manifestations. The internalization of SARS-CoV-2 is initiated by the binding of the virus spike protein to angiotensin converting enzyme 2 (ACE2) on the membrane of host cells including endothelial cells throughout cerebral capillaries. ACE2 is internalized along with the virus thereby leading to a state of ACE2 deficiency. ACE2 is a critical member of the renin-angiotensin system (RAS). This enzyme catabolizes the octapeptide hormone angiotensin-[1-8] thereby protecting cells and tissues from the vasoconstrictor, pro-inflammatory and pro-thrombotic effects of overactive angiotensin type 1 receptors (AT1Rs). Blocking AT1Rs with an AT1R antagonist protects mice from behavioral impairments due to ACE2 deficiency. Lipopolysaccharide (LPS) causes microglia activation and neuronal cell loss and is widely used as an experimental model of neuroinflammation. The brain pathophysiology induced by LPS shares many similarities with SARS-CoV-2 infection. We hypothesize that under conditions of reduced ACE2 (i.e., ACE2 knockout mice or SARS-CoV-2-infected hamsters), AT1R activity is upregulated in the microvasculature. In the presence of an inflammatory insult (i.e., LPS or SARS-CoV-2), AT1Rs promote endothelial dysfunction in the microvasculature through pro-inflammatory and pro-thrombotic signaling pathways leading to blood brain barrier injury. Deficits in cognition and increased anxiety ensue. We will test this overall hypothesis through the following specific aims: Determine the mechanisms of the pro-injury (Aim 1) and protective (Aim 2) arms of the RAS that regulate the pathophysiology of the brain in animal models of neuroinflammation and COVID-19. (Aim 3) Determine the mechanisms underlying the effects of biological sex and age in the brain pathophysiology induced by LPS and SARS-CoV-2. Studying RAS mechanisms in the brain will provide insight into on-going and future clinical trials of therapeutics for treating brain injury associated with COVID-19 and other diseases of neuroinflammation. In addition, focusing on mechanisms underlying the effects of biological sex and age on microvasculature pathophysiology in models of neuroinflammation and COVID-19 will shed light into why male sex and age are major risk factors for COVID-19 severity.

SARS-CoV-2 是当前 COVID-19 大流行的病毒，不仅影响外周组织，还影响以大脑为目标，引起微血管病变、微出血和神经系统表现。这 SARS-CoV-2 的内化是通过病毒刺突蛋白与血管紧张素转化蛋白的结合启动的宿主细胞膜上的酶 2 (ACE2)，包括整个脑毛细血管的内皮细胞。 ACE2 与病毒一起内化，从而导致 ACE2 缺乏状态。 ACE2是关键成员肾素-血管紧张素系统（RAS）。该酶分解代谢八肽激素血管紧张素-[1-8] 从而保护细胞和组织免受血管收缩、促炎和促血栓形成的影响过度活跃的 1 型血管紧张素受体 (AT1R)。用 AT1R 拮抗剂阻断 AT1R 可保护小鼠免受 ACE2 缺乏导致的行为障碍。脂多糖 (LPS) 导致小胶质细胞激活并神经元细胞损失，被广泛用作神经炎症的实验模型。脑病理生理学 LPS 诱导的病毒与 SARS-CoV-2 感染有许多相似之处。我们假设在以下条件下 ACE2 减少（即 ACE2 敲除小鼠或 SARS-CoV-2 感染仓鼠），AT1R 活性上调微血管系统。在存在炎症损伤（即 LPS 或 SARS-CoV-2）的情况下，AT1R 会促进通过促炎症和促血栓信号通路导致微血管内皮功能障碍导致血脑屏障损伤。随之而来的是认知缺陷和焦虑增加。我们将对此进行整体测试通过以下具体目标进行假设：确定促损伤的机制（目标 1）和 RAS 的保护性（目标 2）臂，在动物模型中调节大脑的病理生理学神经炎症和 COVID-19。（目标 3）确定生物性别影响的潜在机制 LPS 和 SARS-CoV-2 诱导的大脑病理生理学中的年龄和年龄。研究大脑中的 RAS 机制将深入了解正在进行和未来的治疗与脑损伤相关的疗法的临床试验 COVID-19 和其他神经炎症疾病。此外，重点关注影响背后的机制神经炎症和 COVID-19 模型中生物性别和年龄对微血管病理生理学的影响将揭示为什么男性性别和年龄是 COVID-19 严重程度的主要风险因素。