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）疾病的发病机理的特征是免疫反应失调 其中包括抑制先天免疫系统，导致“免疫麻痹”和 “细胞因子风暴”的炎症途径的矛盾激活。目标的目标 计划项目是为了研究失调的免疫响应的分子机制 EBOV感染。 EBOV感染必须在生物安全水平4/动物生物安全水平下进行 4（BSL-4/absl-4）根据政府和机构生物安全性，生物安全性 和选择代理法规；因此，该程序项目需要BSL-4核心（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，该设施是 德克萨斯大学医学分公司（UTMB）。核心B与研究之间的相互作用 项目（RPS）将由行政核心（核心A）协调。 计划项目中包括的努力的基础是进行主要感染 来自EBOV的被识别的人类受试者的免疫和非免疫细胞，以及一个具有A的突变体 残疾人干扰素抑制域。接下来，细胞和组织将取自恒河猕猴 被相同病毒感染，该病毒将用于完成体外数据。感染的细胞将 用于转录（研究项目[RP] 1），转录后（RP2）和 翻译后机制（RP3）导致对EBOV的免疫反应失调。这 实验程序的初始步骤（涉及传染性材料） 将在体外会导致基因表达水平上失调反应的关键节点进行体外的反应失调 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。 在核心B中将执行的程序对于实现主要目标至关重要 拟议的研究，包括：（a）转录机制的详细知识 对EBOV的免疫反应失调，（b）阐明转录后机制的作用 在对EBOV的免疫反应失调中，（c）阐明翻译后的作用 对EBOV的免疫反应失调的机制以及（d）建筑物和实验 验证EBOV感染和其他严重病毒的综合模型 感染，例如Marburg，Lassa Fever，Dengue和Covid-19。核心B特定目标的完成 将为RP1，RP2和RP3提供关键支持，以确定转录的作用， 转录后和翻译后机制对EBOV的免疫反应失调。