Core B: Biosafety Level 4 Core

核心 B：生物安全 4 级核心

• 批准号: 10188756
• 负责人: Alexander Bukreyev
• 金额: $ 21.56万
• 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/10188756
• 关键词: Animal Model; Animals; Blood donor; COVID-19; Cells; Characteristics; Complement; Containment; Data; 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; Institutes; 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; Primary Infection; Procedures; Regulation; Research; Research Project Grants; Resources; Role; Sampling; Science; Sea; 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; 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) 疾病的发病机制以免疫反应失调为特征 其中包括抑制先天免疫系统导致“免疫麻痹”和 矛盾的是“细胞因子风暴”特征的炎症途径的激活。此举的目标 项目旨在研究免疫反应失调的分子机制 埃博拉病毒感染。 EBOV 感染必须在生物安全 4 级/动物生物安全级别下进行 4 (BSL-4/ABSL-4) 符合政府和机构生物安全、生物安保的遏制 并选择代理规则；因此，该计划项目需要 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 德克萨斯大学医学分部 (UTMB)。核心 B 与研究之间的互动 项目 (RP) 将由行政核心（核心 A）进行协调。 该计划项目的基础工作将是进行原发性感染 来自未识别的携带埃博拉病毒和突变体的人类受试者的免疫和非免疫细胞 禁用干扰素抑制域。接下来，将从恒河猴身上获取细胞和组织 感染相同病毒，这将用于补充体外数据。被感染的细胞会 用于转录（研究项目 [RP]1）、转录后（RP2）和 导致对 EBOV 免疫反应失调的翻译后机制 (RP3)。这 实验程序的初始步骤，涉及所有 RP 和目标的传染性材料 将进行导致体外基因表达水平失调反应的关键节点 在 GNL BSL-4 设施中。靶向的体内验证将在小鼠和恒河猴中进行 猕猴将在 GNL ABSL-4 设施中进行。 将在核心 B 中执行的程序对于实现核心 B 的主要目标至关重要 拟议的研究，包括：（a）导致转录机制的详细知识 对埃博拉病毒的免疫反应失调，(b) 阐明转录后机制的作用 在针对 EBOV 的免疫反应失调中，(c) 阐明翻译后蛋白的作用 对埃博拉病毒免疫反应失调的机制，以及（d）构建和实验 验证 EBOV 感染和其他严重病毒发病机制的综合模型 感染，例如马尔堡病毒、拉沙热、登革热和 COVID-19。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、 对埃博拉病毒免疫反应失调的转录后和翻译后机制。