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:10602482
- 负责人:
- 金额:$ 221.31万
- 依托单位:
- 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:
- 关键词:2019-nCoVAcuteAddressAfricaAlternative SplicingApoptosisBehaviorBioinformaticsCOVID-19COVID-19 pandemicCellsCessation of lifeCollaborationsCommunicationComplexDataDemocratic Republic of the CongoDendritic CellsDevelopmentDisease OutbreaksEbola Hemorrhagic FeverEbola virusEbola virus envelope glycoproteinEpigenetic ProcessEvaluationEventExperimental DesignsGene ExpressionGenetic TranscriptionHistone DeacetylaseHumanImmuneImmune ToleranceImmune responseIndividualInfectionInflammationInterferonsInvestigationKnowledgeLassa virusLeadLymphopeniaMarburgvirusMass Spectrum AnalysisMassive Parallel SequencingModelingModificationMolecularNF-kappa BOutcomePaintPathogenesisPathogenicityPathologicPhosphorylationPopulationPost-Translational Protein ProcessingProgram Research Project GrantsPublic HealthRNAResearchResearch Project GrantsRoleRunningSamplingStrategic PlanningT-LymphocyteTLR4 geneTestingTissuesTranslation AlterationUbiquitinationValidationViral Hemorrhagic FeversVirusVirus DiseasesWorkantagonistcell typecytokineepidemic virusexperimental studygene productimproved outcomeindividual responsemRNA Translationmedical countermeasurenetwork modelsnonhuman primatenovel therapeuticsoutbreak controlposttranscriptionalprogramsproteogenomicsresponsetooltranscription 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: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、转录后和翻译后的改变会产生反作用
免疫细胞的反应,导致失调的免疫反应,这自相矛盾地产生“免疫”
瘫痪“和过度炎症。为了解决这一假设,本文提出了三个研究项目。研究
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,每个都有贡献
对埃博拉病毒失调的免疫反应。免疫反应失调是大多数
在埃博拉病毒病中观察到的发病机制。
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,以及实验的初始步骤,涉及感染
病毒。重要的是,核心B将提供来自同一实验的每个研究项目的样本
确保每个项目的数据可以直接进行比较的样本-这是本P01的独特功能
程序。蛋白质组学核心(核心C)将负责大规模并行测序和质量
以光谱为基础的研究。生物信息学和建模核心(核心D)是生成工具的关键
用于实验设计,包括对OMICS实验的统计帮助,分析OMICS数据
并将OMICS数据集成到网络中,对感染的各种细胞群体的行为进行建模
EBOV。在核心D中所做的工作将合成一个模型来解释转录、转录后和
单个细胞群体的翻译后反应导致免疫失调。全面的
这一合作努力描绘的图景将彻底改变我们对霍乱免疫发病机制的理解
严重的急性病毒感染(例如,新冠肺炎中出现的免疫失衡)。行政核心(核心A)
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,对项目的各个组成部分进行管理。
预期的结果将大大有助于我们了解
针对EBOV感染的免疫发病机制发展提出有效的对策。预期中的
结果将包括:(1)详细了解导致免疫失调的转录机制。
对EBOV的应答,(2)阐明转录后机制在免疫失调中的作用
对EBOV的应答,(3)阐明翻译后机制在免疫失调中的作用
对EBOV的反应,以及(4)对已确定的致病机制及其靶向的实验验证。
拟议的紧密协调和全面的分析以前从未对任何病毒进行过。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Next-generation sequencing: A new avenue to understand viral RNA-protein interactions.
- DOI:10.1016/j.jbc.2022.101924
- 发表时间:2022-05
- 期刊:
- 影响因子:0
- 作者:Zhou Y;Sotcheff SL;Routh AL
- 通讯作者:Routh AL
The anti-immune dengue subgenomic flaviviral RNA is present in vesicles in mosquito saliva and is associated with increased infectivity.
- DOI:10.1371/journal.ppat.1011224
- 发表时间:2023-03
- 期刊:
- 影响因子:6.7
- 作者:
- 通讯作者:
Early Splicing Complexes and Human Disease.
- DOI:10.3390/ijms241411412
- 发表时间:2023-07-13
- 期刊:
- 影响因子:5.6
- 作者:
- 通讯作者:
Role of Alternative Splicing in Regulating Host Response to Viral Infection.
- DOI:10.3390/cells10071720
- 发表时间:2021-07-08
- 期刊:
- 影响因子:6
- 作者:Liao KC;Garcia-Blanco MA
- 通讯作者:Garcia-Blanco MA
RNA Viruses, Pandemics and Anticipatory Preparedness.
- DOI:10.3390/v14102176
- 发表时间:2022-09-30
- 期刊:
- 影响因子:0
- 作者:Garcia-Blanco MA;Ooi EE;Sessions OM
- 通讯作者:Sessions OM
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Alexander Bukreyev其他文献
Alexander Bukreyev的其他文献
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{{ truncateString('Alexander Bukreyev', 18)}}的其他基金
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
- 批准号:
10394314 - 财政年份:2021
- 资助金额:
$ 221.31万 - 项目类别:
Research Project 1: Role of Epigenetic and Transcriptional Mechanisms in the Pathogenesis of Ebola Virus Disease
研究项目1:表观遗传和转录机制在埃博拉病毒疾病发病机制中的作用
- 批准号:
10602491 - 财政年份:2021
- 资助金额:
$ 221.31万 - 项目类别:
Research Project 1: Role of Epigenetic and Transcriptional Mechanisms in the Pathogenesis of Ebola Virus Disease
研究项目1:表观遗传和转录机制在埃博拉病毒疾病发病机制中的作用
- 批准号:
10188759 - 财政年份:2021
- 资助金额:
$ 221.31万 - 项目类别:
Research Project 1: Role of Epigenetic and Transcriptional Mechanisms in the Pathogenesis of Ebola Virus Disease
研究项目1:表观遗传和转录机制在埃博拉病毒疾病发病机制中的作用
- 批准号:
10394319 - 财政年份:2021
- 资助金额:
$ 221.31万 - 项目类别:
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