Effect of Covid-19 engagement of ACE2 on brain health and pathology

Covid-19 与 ACE2 的结合对大脑健康和病理学的影响

基本信息

批准号：
10151985
负责人：
Betty Diamond
金额：
$ 19.65万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-08 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10151985
关键词：
AGTR2 gene Address Affect Alzheimer&apos s Disease Angiotensin I Angiotensin II Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensins Anti-Inflammatory Agents Antibodies Antihypertensive Agents Behavior Binding Blood - brain barrier anatomy Brain Brain Pathology COVID-19 Cardiac Cells Chronic Cleaved cell Cognition Coronavirus Data Dendrites Disease Drug usage Effectiveness Enzymes Epithelial Cells Exhibits G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Genetic Transcription Goals Homeostasis Human Impairment Individual Inflammation Inflammatory Response Interferons Mediating Membrane Microglia Modeling Mus Nerve Degeneration Neuraxis Neurons Neuropsychiatric Systemic Lupus Erythematosus Pathologic Pathology Pathway interactions Penetration Peptide Hydrolases Peptides Peptidyl-Dipeptidase A Peripheral Nervous System Pharmaceutical Preparations Positron-Emission Tomography Process Production Proteins Renal Tissue Renin-Angiotensin System Role Sepsis Survivors System TNF gene Therapeutic Effect Tissues Viral Virus arm base brain cell brain endothelial cell brain health cytokine enzyme pathway human disease human subject immune activation improved in vivo interest mouse model neuroinflammation prevent programs receptor receptor binding uptake

项目摘要

Abstract There are mechanisms in the brain that regulate interactions between neurons and microglial cells and promote homeostasis. These are perturbed in several diseases including neuropsychiatric lupus, NPSLE, studied in this PPG, and following sepsis. Many conditions of neuroinflammation are characterized by microglial activation, and, as a consequence of this activation, by neuronal dendritic pruning and an impaired blood brain barrier. Interestingly, a pathway regulating homeostasis in the brain and dysregulated by neuroinflammation is the renin-angiotensin system. Angiotensin II is generated by angiotensin converting enzyme, ACE, and binds to a receptor AT-1 to enhance inflammation. ACE inhibitors or angiotensin receptor blockers, ARBs, can improve neuroinflammation by either decreasing production or neutralizing angiotensin II. In this pathway, ACE2, a membrane-bound protease, also functions to destroy angiotensin and to generate a small angiotensin peptide, ang1-7, that is anti-inflammatory. ACE2 is the cellular receptor for Covid-19, and binds the viral spike protein, S, more specifically, the receptor binding domain, RBD. This study will examine the binding of S and RBD to normal mouse brain and to mouse brain mimicking NPSLE or sepsis survival. We will further study whether engagement by S or RBD alters the functional state of neurons, microglia and brain endothelial cells. Finally, we ask whether the use of ACE inhibitors or ARBs alters S or RBD binding, and whether S or RBD impair the efficacy of these medications in halting or reversing the neurodegenerative process in NPSLE and in sepsis survivors. This study cannot be performed in humans, but it has important translational implications.

抽象的大脑中有一些调节神经元与小胶质细胞之间相互作用的机制细胞并促进稳态。这些在多种疾病中受到干扰 NPSLE的神经精神狼疮，在此PPG和败血症之后进行了研究。许多条件神经炎症的特征是小胶质细胞激活，因此，激活，通过神经元树突修剪和血脑屏障受损。有趣的是，调节大脑中体内稳态的途径和神经炎症失调的途径是肾素 - 血管紧张素系统。血管紧张素II是由血管紧张素转化酶，ACE，并与受体AT-1结合以增强炎症。 ACE抑制剂或血管紧张素受体阻滞剂ARB可以通过减少产量或中和来改善神经炎症血管紧张素II。在此途径中，ACE2（一种膜结合的蛋白酶）也起作用可破坏血管紧张素并产生一种抗炎作用的小血管紧张素肽Ang1-7。 ACE2是COVID-19的细胞受体，并结合病毒尖峰蛋白S，更具体地，更具体地说受体结合结构域RBD。这项研究将检查S和RBD与正常的结合小鼠脑和小鼠大脑模仿NPSLE或败血症。我们将进一步学习 S或RBD的参与是否会改变神经元，小胶质细胞和大脑的功能状态内皮细胞。最后，我们询问使用ACE抑制剂或ARB是否改变S或RBD 具有约束力，以及S或RBD是否会损害这些药物停止或逆转的功效 NPSLE和败血症幸存者中的神经退行性过程。这项研究不能是在人类中表演，但具有重要的翻译意义。