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

• 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
• 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' 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

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.

摘要 大脑中有一些机制可以调节神经元和小胶质细胞之间的相互作用， 细胞和促进体内平衡。这些在几种疾病中受到干扰，包括 神经精神性狼疮，NPSLE，在此PPG中研究，并在败血症后。许多条件 神经炎症的特征是小胶质细胞活化，因此， 激活，通过神经元树突修剪和受损的血脑屏障。有趣的是，一 调节脑内稳态和神经炎症失调的途径是 血管紧张素系统血管紧张素II是由血管紧张素转换酶，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 阻断剂ARB可以通过减少产生或中和 血管紧张素II在这一途径中，ACE 2，一种膜结合蛋白酶，也起到破坏 血管紧张素，并产生一种小的血管紧张素肽，血管紧张素1 -7，这是抗炎。 ACE 2是Covid-19的细胞受体，更具体地说， 受体结合域RBD。本研究将检查S和RBD与正常人的结合， 小鼠脑和模拟NPSLE或脓毒症存活的小鼠脑。我们将进一步研究 S或RBD的参与是否改变了神经元、小胶质细胞和大脑的功能状态 内皮细胞最后，我们问是否使用ACE抑制剂或ARB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 NPSLE和脓毒症幸存者的神经退行性过程。这项研究不能 在人类中进行，但它具有重要的翻译意义。