MiRNA-based Therapeutics for SARS-CoV-2 S1 mediated neuroinflammation and beta-amyloid production

基于 miRNA 的 SARS-CoV-2 S1 介导的神经炎症和 β-淀粉样蛋白产生疗法

• 批准号: 10433303
• 负责人: Eleni Markoutsa
• 金额: $ 7.48万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433303
• 关键词: 2019-nCoV; Abeta synthesis; Algorithms; Alzheimer' s disease risk; Amyloid; Amyloid deposition; Astrocytes; Attenuated; Bioinformatics; Biological Assay; Brain; COVID-19; COVID-19 impact; COVID-19 survivors; COVID-19 therapeutics; Cells; Cerebrospinal Fluid; Cessation of life; Chronic; Data; Dementia; Development; Down-Regulation; Encephalitis; Family; Feedback; Future; Genes; Homeostasis; Human; Immune; Immune response; Immune signaling; Infection; Inflammation; Inflammatory; Interleukin-6; Lead; Light; Long-Term Effects; Luciferases; MAP Kinase Gene; MAPK1 gene; MAPK8 gene; Measures; Mediating; Mediator of activation protein; MicroRNAs; Microglia; Mus; NF-kappa B; Neuraxis; Neuroimmune; Neurologic Symptoms; Pathway interactions; Persons; Process; Production; Proteins; Proteolytic Processing; Quantitative Reverse Transcriptase PCR; Regulation; Reporter; Respiratory Signs and Symptoms; Role; SARS-CoV-2 infection; Signal Pathway; Signal Transduction; Stains; Structural Protein; TLR4 gene; TNF gene; Testing; Therapeutic Intervention; Time; Transcript; Validation; Viral Proteins; Virus; Work; abeta accumulation; bioinformatics tool; brain parenchyma; coronavirus therapeutics; cytokine; cytokine release syndrome; effectiveness validation; engineered exosomes; exosome; experimental study; glial activation; high risk; in vitro testing; in vivo; innovation; insight; member; neuroinflammation; novel; p38 Mitogen Activated Protein Kinase; pandemic disease; pathogen; response; therapeutic miRNA; tool; viral RNA

Project summary/Abstract There is ample evidence that SARS-CoV-2, the causative agent of COVID-19, causes neurological symptoms but there is insufficient evidence that the virus can directly infect the brain. It has been suggested that neurological symptoms might be due to additional factors such as cytokine storm, neuroimmune stimulation, and systemic SARS-CoV-2 infection, rather than by direct CNS damage caused by the virus. The S protein is the main antigenic component of SARS- CoV-2 structural protein and its proteolytic processing allows the S1 subunit to dissociate, which then triggers the S2 subunit rearrangement that is required for fusion. Also, TLR4 is the most important member of the TLR family for pathogen recognition and helps to provide first line defense against infections through inflammatory factors induction. Herein, we propose to test the hypothesis that the cleaved S1 subunit itself enters the brain parenchyma causing neuroinflammation and b-amyloid accumulation and TLR4-targeted microRNA(s) can inhibit these processes. This hypothesis will be tested in two specific aims. First, we will test if S1 directly interacts with TLR4 in microglia and initiates immune responses that leads to excessive activation of the pathway, which disrupts immune homeostasis and results in chronic brain inflammation and b-amyloid accumulation. Second, we will test the role of specific miRNAs, selected using bioinformatics prediction tools, in regulating the S1-initiated neuroinflammation. After experimental validation of miRNA targets, specific miRNAs will be enriched in exosomes and tested for their ability to end the positive feedback loop between inflammation and b-amyloid production. The results are expected to provide mechanistic insights into the COVID-19 effects on neuroinflammation and dementia and lead to the development of miRNA therapeutics against covid-induced regulatory loop between inflammation and b-amyloid production.

项目概要/摘要 有充分的证据表明，SARS-CoV-2，COVID-19的病原体， 神经系统症状，但没有足够的证据表明病毒可以直接感染大脑。 有人认为，神经系统症状可能是由于其他因素，如 细胞因子风暴，神经免疫刺激和系统性SARS-CoV-2感染，而不是通过 病毒引起的中枢神经系统直接损伤。S蛋白是SARS的主要抗原成分， CoV-2结构蛋白及其蛋白水解过程允许S1亚基解离， 然后触发融合所需的S2亚基重排。另外，TLR 4是 TLR家族的重要成员，用于病原体识别， 通过炎症因子诱导防御感染。在此，我们建议测试 假设裂解的S1亚基本身进入脑实质， 神经炎症和b-淀粉样蛋白积累和TLR 4靶向的microRNA可以抑制这些 流程.这一假设将在两个具体目标中得到检验。第一、 我们将测试S1是否直接 与小胶质细胞中的TLR 4相互作用并启动导致过度激活的免疫应答 破坏免疫稳态并导致慢性脑炎症 和b-淀粉样蛋白积聚。其次，我们将测试特定的miRNAs的作用，使用 生物信息学预测工具，在调节S1启动的神经炎症。后 miRNA靶点的实验验证，特异性miRNA将在外来体中富集， 测试它们结束炎症和b-淀粉样蛋白之间正反馈循环的能力 生产预计这些结果将为COVID-19的影响提供机理见解 神经炎症和痴呆症，并导致开发针对 covid诱导的炎症和b-淀粉样蛋白产生之间的调节环。