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.

抽象的大脑中有调节神经元和小胶质细胞之间相互作用的机制细胞并促进体内平衡。这些在多种疾病中受到干扰，包括本次 PPG 中研究了神经精神性狼疮 (NPSLE) 以及脓毒症。许多条件神经炎症的特点是小胶质细胞激活，因此通过神经元树突修剪和受损的血脑屏障来激活。有趣的是，一个调节大脑稳态并因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 由血管紧张素转换酶 ACE 产生，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 可以通过减少产生或中和来改善神经炎症血管紧张素II。在此途径中，ACE2（一种膜结合蛋白酶）也具有破坏血管紧张素并生成一种小血管紧张素肽 ang1-7，具有抗炎作用。 ACE2 是 Covid-19 的细胞受体，并结合病毒刺突蛋白 S，更具体地说，受体结合域，RBD。本研究将检查 S 和 RBD 与正常细胞的结合小鼠大脑和模拟 NPSLE 或败血症生存的小鼠大脑。我们将进一步研究 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 是否会改变 S 或 RBD 结合，以及 S 或 RBD 是否会损害这些药物在停止或逆转方面的功效 NPSLE 和脓毒症幸存者的神经退行性过程。这项研究不能在人类身上进行，但它具有重要的转化意义。