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 大脑中有调节神经元和小胶质细胞之间相互作用的机制。 细胞和促进动态平衡。它们在几种疾病中受到干扰，包括 神经精神性狼疮，NPSLE，在这个PPG中研究，并在脓毒症后。许多情况下 神经炎症的特征是小胶质细胞的激活，因此 通过神经元树突修剪和血脑屏障受损而激活。有趣的是，一个 调节大脑内动态平衡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由血管紧张素转换酶、血管紧张素转换酶、 并与受体AT-1结合以增强炎症。血管紧张素转换酶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。在这一途径中，ACE2，一种膜结合的蛋白酶，也起到破坏 血管紧张素和产生一种抗炎的小血管紧张素，Ang1-7。 血管紧张素转换酶2是新冠肺炎的细胞受体，与病毒尖峰蛋白S结合，更具体地说， 受体结合域，RBD。本研究将考察S和红斑狼疮与正常人的结合 小鼠脑和小鼠脑模拟NPSLE或脓毒症存活。我们将进一步研究 S或RBD参与是否改变神经元、小胶质细胞和脑的功能状态 内皮细胞。最后，我们询问血管紧张素转换酶抑制剂或ARB的使用是否会改变S或RBD 结合，以及S或RBD是否损害这些药物的止血或逆转作用 NPSLE和脓毒症幸存者的神经退变过程。这项研究不能 在人类身上进行，但它具有重要的翻译意义。