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：
10617754
负责人：
JUAN M SAAVEDRA
金额：
$ 62.36万
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/10617754
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 impact COVID-19 pandemic COVID-19 patient COVID-19 risk COVID-19 severity Cells Central Nervous System Cerebral hemisphere hemorrhage Cerebrovascular Disorders Cerebrum Clinical Trials Coagulation Process Cognition Cognitive Complement Activation Confusion Cytoprotection Disease Endothelial Cells Endothelium Enzymes Exhibits Experimental Models Fibrin Functional disorder Future Gram-Negative Bacteria Hamsters Headache Hemorrhage Hippocampus Hormonal Hormones Impairment Infiltration Inflammation Inflammatory Injury Interleukin-1 beta Interleukin-6 Ischemic Stroke Knockout Mice Lesion Light Lipopolysaccharides Lung Membrane Memory Microglia Modeling Mus NF-kappa B Neurologic Symptoms Neurons Pathology Pathway interactions Peripheral Pharmacologic Substance Platelet Activation Play Production Proteins Prothrombin Receptor, Angiotensin, Type 1 Renin-Angiotensin System Reporting Research Role SARS-CoV-2 infection Signal Pathway Signal Transduction Symptoms TLR2 gene TLR4 gene Testing Therapeutic Thrombin Thrombosis Tissues Vasoconstrictor Agents Venous Thrombosis Viral Virus arm behavioral impairment biological adaptation to stress biological sex blood-brain barrier function brain endothelial cell brain parenchyma cerebral capillary cerebral microvasculature cerebrovascular cytokine endothelial dysfunction experimental study immunothrombosis insight male member neuroinflammation neuron loss neuroprotection overexpression pandemic disease sex

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，不仅影响外周组织靶向大脑，引起微血管病变，微毛和神经系统表现。这 SARS-COV-2的内在化是通过病毒峰值蛋白与血管紧张素转化的结合而引发的宿主细胞的膜上的酶2（ACE2），包括整个脑毛细血管的内皮细胞。 ACE2与病毒一起被内化，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）。这种酶会分解八磷酸激素血管紧张素 - [1-8] 从而保护细胞和组织免受血管收缩剂的影响过度活跃的血管紧张素1型受体（AT1RS）。用AT1R拮抗剂阻止AT1RS保护小鼠免受 ACE2缺乏症引起的行为障碍。脂多糖（LPS）引起小胶质细胞激活和神经元细胞丧失，被广泛用作神经炎症的实验模型。大脑病理生理学 LPS诱导的与SARS-COV-2感染的许多相似之处。我们假设在 ACE2减少（即ACE2敲除小鼠或SARS-COV-2感染的仓鼠），AT1R活性在微脉管系统。在存在炎症性侮辱（即LPS或SARS-COV-2）的情况下，AT1RS促进通过促炎和促脉症信号通路，微脉管系统中的内皮功能障碍导致血脑屏障损伤。随之而来的是认知和增加焦虑的缺陷。我们将整体测试这个通过以下特定目的假设：确定亲伤的机制（AIM 1）和在动物模型中调节大脑病理生理学的RA的保护性（AIM 2）臂神经炎症和COVID-19。（AIM 3）确定生物学作用的基础机制 LPS和SARS-COV-2诱导的脑病理生理学年龄。研究大脑中的RAS机制将提供有关治疗脑损伤的持续和未来临床试验的见解 Covid-19和其他神经炎症的疾病。另外，关注效果的基础机制神经炎症模型和covid-19的生物性别和年龄在微脉管病理生理学上将阐明男性和年龄是19009年严重程度的主要危险因素。