Core B: Biosafety Level 4 Core

核心 B：生物安全 4 级核心

• 批准号: 10602485
• 负责人: Alexander Bukreyev
• 金额: $ 21.52万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602485
• 关键词: Animal Model; Animals; Blood donor; COVID-19; Cells; Characteristics; Complement; Containment; Data; Decontamination; Dengue; Disabled Persons; Doctor of Philosophy; Ebola Hemorrhagic Fever; Ebola virus; Emerging Communicable Diseases; Funding; Gene Expression; Genetic Transcription; Goals; Government; Human; Immune; Immune Tolerance; Immune response; Immunity; In Vitro; Infection; Inflammatory; Infrastructure; Innate Immune System; Institution; Interferons; International; Investigation; Knowledge; Laboratories; Lassa Fever; Lead; Macaca mulatta; Marburgvirus; Medical; Modeling; Molecular; Mus; National Institute of Allergy and Infectious Disease; Organ; Pathogenesis; Pathway interactions; Procedures; Regulation; Research; Research Project Grants; Resources; Role; Sampling; Science; Senior Scientist; Texas; Tissues; Training; United States National Institutes of Health; Universities; Vaccines; Validation; Viral; Virus; Virus Diseases; Work; biodefense; biosafety level 4 facility; biosecurity; career; cytokine release syndrome; experience; experimental study; human subject; in vivo; member; mutant; posttranscriptional; professor; programs; proteogenomics; repository; response

BSL-4 CORE (Core B): PROJECT SUMMARY/ABSTRACT The pathogenesis of Ebola virus (EBOV) disease is characterized by a dysregulated immune response that includes the suppression of the innate immune system leading to “immune paralysis” and paradoxically activation of inflammatory pathways characteristic of a “cytokine storm”. The goal of this Program Project is to investigate the molecular mechanisms of the dysregulated immune response to EBOV infections. EBOV infections must be performed under Biosafety Level 4/Animal Biosafety level 4 (BSL-4/ABSL-4) containment in accordance with government and institutional biosafety, biosecurity and select agent regulations; therefore, this Program Project requires a BSL-4 Core (Core B). Core B will use the BSL-4 and ABSL-4 facilities of the Galveston National Laboratory (GNL), which is part of the University of Texas Medical Branch (UTMB). Interactions between Core B and the Research Projects (RPs) will be coordinated by the Administrative Core (Core A). Fundamental to the efforts included in the Program Project will be performing infections of primary immune and nonimmune cells from deidentified human subjects with EBOV and a mutant with a disabled interferon-inhibiting domain. Next, cells and tissues will be taken from rhesus macaques infected with the same viruses, which will be used to complement in vitro data. The infected cells will be used for investigation of transcriptional (Research Project [RP]1), posttranscriptional (RP2), and posttranslational mechanisms (RP3) that lead to the dysregulated immune response to EBOV. The initial steps of the experimental procedures, which involve infectious materials, for all RPs and targeting of critical nodes leading to dysregulated responses at gene expression levels in vitro will be performed in GNL BSL-4 facilities. The in vivo validation of the targeting will be performed in mice and rhesus macaques will be performed in GNL ABSL-4 facilities. The procedures that will be performed in Core B are critical for achieving the major goals of the proposed studies, including: (a) detailed knowledge of transcriptional mechanisms leading to the dysregulated immune response to EBOV, (b) elucidation of the role of posttranscriptional mechanisms in the dysregulated immune response to EBOV, (c) elucidation of the role of posttranslational mechanisms in the dysregulated immune response to EBOV, and (d) building and experimental validation of a comprehensive model for the pathogenesis of EBOV infection and other severe viral infections, such as Marburg, Lassa fever, dengue, and COVID-19. Completion of Core B Specific Aims will provide critical support for RP1, RP2, and RP3 to identify the role of transcriptional, posttranscriptional, and posttranslational mechanisms in the dysregulated immune response to EBOV.

BSL-4核心(核心B)：项目摘要/摘要 埃博拉病毒(EBOV)病的发病机制以免疫反应失调为特征 这包括抑制先天免疫系统，导致“免疫瘫痪”和 自相矛盾的是，炎症通路被激活，这是“细胞因子风暴”的特征。这样做的目的是 项目是研究失调性免疫反应的分子机制 EBOV感染。EBOV感染必须在生物安全级别4/动物生物安全级别下进行 4(BSL-4/ABSL-4)根据政府和机构的生物安全、生物安保进行遏制 并选择代理法规；因此，此计划项目需要BSL-4核心(核心B)。核心B 将使用加尔维斯顿国家实验室(GNL)的BSL-4和ABSL-4设施，该实验室是 德克萨斯大学医学部(UTMB)。B芯与研究的相互作用 项目(方案)将由行政核心(核心A)协调。 计划项目中所包括的基本努力将是执行初级感染 来自已确认感染EBOV的人的免疫和非免疫细胞以及1例携带AFP的突变体 禁用干扰素抑制结构域。接下来，将从恒河猴身上提取细胞和组织 感染了同样的病毒，这将被用来补充体外数据。被感染的细胞会 用于研究转录(研究项目[RP]1)、转录后(RP2)和 导致EBOV免疫应答失调的翻译后机制(RP3)。这个 实验程序的初始步骤，涉及传染病材料，适用于所有RP和靶向 将在体外进行导致基因表达水平异常反应的关键节点的研究 在GNL BSL-4设施中。靶向的体内验证将在小鼠和恒河猴身上进行 猕猴将在GNL ABSL-4设施中进行表演。 将在核心B执行的程序对于实现以下主要目标至关重要 拟议研究，包括：(A)详细了解导致基因转录的转录机制 对EBOV的免疫应答失调，(B)转录后机制的作用 在EBOV失调的免疫反应中，(C)阐明翻译后的作用 EBOV免疫应答失调的机制，以及(D)构建和实验 EBOV感染和其他严重病毒致病机制综合模型的验证 感染，如马尔堡、拉沙热、登革热和新冠肺炎。完成核心B的具体目标 将为RP1、RP2和RP3提供关键支持，以确定转录、 EBOV失调免疫反应中的转录后和翻译后机制。