Molecular Mechanisms of the Dysregulated Immune Response to Ebola Virus

埃博拉病毒免疫反应失调的分子机制

基本信息

批准号：
10394314
负责人：
Alexander Bukreyev
金额：
$ 252.83万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
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/10394314
关键词：
2019-nCoV Acute Address Africa Alternative Splicing Apoptosis Behavior Bioinformatics COVID-19 COVID-19 pandemic Cells Cessation of life Communication Complex Containment Data Democratic Republic of the Congo Dendritic Cells Development Disease Outbreaks Ebola Hemorrhagic Fever Ebola virus Ebola virus envelope glycoprotein Epidemic Epigenetic Process Evaluation Event Experimental Designs Gene Expression Genetic Transcription Genetic Translation Histone Deacetylase Human Immune Immune Tolerance Immune response Individual Infection Inflammation Investigation Knowledge Lassa virus Lead Lymphopenia Marburgvirus Mass Spectrum Analysis Massive Parallel Sequencing Modeling Modification Molecular Outcome Paint Pathogenesis Pathogenicity Pathologic Phosphorylation Population Post-Translational Protein Processing Program Research Project Grants Public Health RNA Research Research Project Grants Role Running Sampling Strategic Planning T-Lymphocyte TLR4 gene Testing Tissues Ubiquitination Validation Viral Hemorrhagic Fevers Virus Virus Diseases Work base cell type cytokine experimental study gene product improved outcome individual response interferon antagonist medical countermeasure network models nonhuman primate novel therapeutics programs proteogenomics response tool transcription factor

项目摘要

OVERALL: PROJECT SUMMARY/ABSTRACT The central hypothesis of the proposed P01 Program is that Ebola virus infection leads to cell-type specific transcriptional, posttranscriptional, and posttranslational alterations that create aberrant counterproductive responses of immune cells, leading to a dysregulated immune response, which paradoxically produces “immune paralysis” and hyperinflammation. To address the hypothesis, three Research Projects are proposed. Research Project 1 focuses on pathogenic mechanisms at the transcriptional level, while Research Project 2 focuses on posttranscriptional events, and Research Project 3 focuses on posttranslational modifications, each contributing to the dysregulated immune response to Ebola virus. The dysregulated immune response is responsible for most of the pathogenesis observed in Ebola virus disease. All projects require the BSL-4 Core (Core B), which will be responsible for performing infections of human immune and nonimmune cells, nonhuman primates, and the initial steps of experiments that involve infectious virus. Importantly, Core B will provide each of the research projects samples from the same experimental samples insuring that data from each project can be compared directly—this is a unique feature of this P01 Program. The Proteogenomics Core (Core C) will be responsible for massive parallel sequencing and mass spectrometry-based studies. The Bioinformatics and Modeling Core (Core D) is critical for generating tools employed in the experimental designs, including statistical help for OMICS experiments, analyzing OMICS data and integrating OMICS data into networks that model the behavior of various cell populations infected with EBOV. The work done in Core D will synthesize a model to explain how transcriptional, posttranscriptional, and posttranslational responses of individual cell populations lead to immune dysregulation. The comprehensive picture painted by this collaborative effort will revolutionize our understanding of the immunopathogenesis of severe acute viral infections (e.g., immune imbalance seen in COVID-19). The Administrative Core (Core A) will be responsible for strategic planning, continual evaluation, and communication and coordination of activities among the various components of the project according to a detailed management plan. The expected outcomes will contribute substantially to our knowledge of the fundamental mechanisms of the immunopathogenesis of EBOV infections toward the development of effective countermeasures. The expected outcomes will include (1) detailed knowledge of transcriptional mechanisms leading to the dysregulated immune response to EBOV, (2) elucidation of the role of posttranscriptional mechanisms in the dysregulated immune response to EBOV, (3) elucidation of the role of posttranslational mechanisms in the dysregulated immune response to EBOV, and (4) experimental validation of the identified pathogenic mechanisms and their targeting. The proposed tightly coordinated and comprehensive analysis has not been done before for any virus.

总体而言：项目摘要/摘要拟议的 P01 计划的中心假设是埃博拉病毒感染导致细胞类型特异性转录、转录后和翻译后改变会产生异常的反作用免疫细胞的反应，导致免疫反应失调，矛盾地产生“免疫反应” 为了解决这一假设，提出了三个研究项目。项目1侧重于转录水平的致病机制，而研究项目2侧重于转录后事件，研究项目 3 侧重于翻译后修饰，每个都贡献对埃博拉病毒的免疫反应失调免疫反应失调是造成大多数的原因。埃博拉病毒病的发病机制。所有项目都需要 BSL-4 核心（核心 B），它将负责执行人类感染免疫和非免疫细胞、非人类灵长类动物以及涉及传染性的实验的初始步骤重要的是，Core B 将为每个研究项目提供来自同一实验的样本。样本确保可以直接比较每个项目的数据——这是 P01 的独特之处蛋白质基因组学核心（核心 C）将负责大规模并行测序和质量分析。基于光谱分析的研究对于生成工具至关重要。用于实验设计，包括 OMICS 实验的统计帮助、分析 OMICS 数据并将 OMICS 数据集成到网络中，对感染病毒的各种细胞群的行为进行建模 Core D 中完成的工作将合成一个模型来解释转录、转录后和转录过程如何进行。单个细胞群的翻译后反应导致免疫失调。这项合作所描绘的图景将彻底改变我们对免疫发病机制的理解严重急性病毒感染（例如，COVID-19 中出现的免疫失衡）。将负责战略规划、持续评估以及活动的沟通和协调根据详细的管理计划，在项目的各个组成部分之间进行协调。预期结果将极大地促进我们对基本机制的了解 EBOV 感染的免疫发病机制有助于制定有效的对策。结果将包括（1）详细了解导致免疫系统失调的转录机制对 EBOV 的反应，(2) 阐明转录后机制在免疫失调中的作用对 EBOV 的反应，(3) 阐明翻译后机制在免疫失调中的作用对埃博拉病毒的反应，(4) 对已确定的致病机制及其靶向的实验验证。之前还没有对任何病毒进行过所提出的紧密协调和全面的分析。