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
基本信息
- 批准号:10188759
- 负责人:
- 金额:$ 42.55万
- 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-nCoVATAC-seqAcuteAddressAnimalsAntiinflammatory EffectApoptosisAreaB-LymphocytesBioinformaticsCell physiologyCellsCessation of lifeChIP-seqChemicalsChromatinCollaborationsCytoplasmDataData AnalysesDendritic CellsDepositionDevelopmentDiseaseEbolaEbola Hemorrhagic FeverEbola virusEbola virus envelope glycoproteinEndothelial CellsEnzymesEpigenetic ProcessEquilibriumGene ActivationGene ExpressionGenesGenetic TranscriptionHepatocyteHumanImmuneImmune ToleranceImmune responseImmunityImmunologyIn VitroInfectionInflammationInflammation MediatorsInflammatoryInterferon-alphaInterferonsInvestigationJointsJournalsKnowledgeLymphopeniaMarburgvirusMediatingMediator of activation proteinMethodsModelingMolecularMusMyelogenousNatureOutcomes ResearchPaperPathogenesisPathogenicityPathologicPharmacologyPhysiologicalProcessProductionProtein IsoformsPublishingResearchResearch PersonnelResearch Project GrantsRoleScienceSignal TransductionSiteT cell responseT-Cell ActivationT-LymphocyteTLR4 geneTestingTopoisomeraseTranscriptional RegulationTranslational RegulationTreatment outcomeViral PathogenesisVirusVirus DiseasesWorkbasecell typecytokinecytokine release syndromeepigenetic regulationepigenomegene repressionhistone methylationin vivoinhibitor/antagonistinnovationkidney cellmRNA Expressionmedical schoolsmonocytenonhuman primatepathogenprogramsproteogenomicsresponsesingle cell analysissingle cell sequencingtranscription factortranscriptometranscriptome sequencingtranscriptomicsvirology
项目摘要
RESEARCH PROJECT 1 (RP1): PROJECT SUMMARY/ABSTRACT
Pathogenesis of the disease caused by Ebola virus (EBOV) is characterized by a multifaceted and contradictory
interplay between the virus and the host. The effect of EBOV infection is characterized by deficient T-cell
responses and lymphopenia, which at least in part results from stimulation by virus-infected dendritic cells whose
maturation is suppressed by interferon-inhibiting domains of the virus. In addition, EBOV infections are
characterized by hyperinflammation, contributed by interaction of the EBOV envelope glycoprotein (GP) with
TLR4 on T cells and possibly by other mechanisms, resulting in massive secretion of cytokines. This
dysregulated immune response results from disruption of transcriptional networks, many caused by alterations
in the epigenome, as evidenced by (1) chemical inhibition of type 1 topoisomerase resulting in reduced
expression of proinflammatory mediators induced by EBOV in infected cells, (2) inhibition of TLR4 signaling,
which is regulated at epigenetic level, promoting survival of EBOV-infected mice, and (3) treatment of EBOV-
infected mice with a global histone methylation inhibitor that upregulates production of IFNα and protects animals
from death.
The central hypothesis of Research Project 1 (RP1) is that cell-specific and gene-specific regulation of
transcription in response to EBOV infection leads to contrasting responses that paradoxically cause a pathogenic
immune response and “immune paralysis”. To address this hypothesis, the epigenetic and transcriptional
landscape during EBOV infections in vitro and in vivo will be characterized. A comprehensive analysis of the
transcriptome alterations and epigenetic changes caused by EBOV infection will be performed in both human
primary cells and specific cell types isolated from infected nonhuman primates. Investigations involving the
expression of mRNAs that encode transcription factors will be done to determine the deposition of epigenetic
marks and their role in gene activation and repression, as well as investigating the effects of chromatin
accessibility on expression and secretion of inflammatory mediators using cells from human donors.
This project will target key transcriptional nodes identified by modeling EBOV infection. The data generated in
vitro and in vivo, together with data from in RP2 and RP3, will be integrated by the Bioinformatics and
Modelling Core (Core D) in a model. The transcriptional networks identified in the model will predict critical
nodes that represent vulnerabilities that will be targeted to modulate cell response and reduce EBOV
pathogenesis. For example, chromatin-resident enzymes and transcription factors that induce expression of
genes causing inflammation and other pathological changes will be targeted.
The study will result in the characterization of epigenetic and transcriptional responses to EBOV; to date no
epigenetic response to any BSL-4 level virus has been characterized. The study will also result in the
development of approaches to treat EBOV disease by targeting host transcriptional and epigenetic functions.
研究项目1(RP1):项目摘要/摘要
埃博拉病毒(Ebola Virus,EBOV)的发病机制具有多方面和矛盾性的特点
病毒和宿主之间的相互作用。EBOV感染的影响以T细胞缺陷为特征
反应和淋巴细胞减少,这至少部分是由病毒感染的树突状细胞刺激引起的,其
成熟受到病毒干扰素抑制结构域的抑制。此外,EBOV感染是
以过度炎症为特征,由EBOV包膜糖蛋白(GP)与
TLR4对T细胞的作用,可能通过其他机制,导致细胞因子的大量分泌。这
免疫反应失调是由转录网络的破坏引起的,许多是由改变引起的
在表观基因组中,如(1)化学抑制1型拓扑异构酶导致减少
EBOV诱导感染细胞中促炎症介质的表达,(2)抑制TLR4信号转导,
它在表观遗传水平上受到调控,促进感染EBOV的小鼠存活,以及(3)治疗EBOV-
感染组蛋白甲基化抑制剂的小鼠上调干扰素α的产生并保护动物
从死亡中脱身。
研究项目1(RP1)的中心假设是细胞特异性和基因特异性调节
对EBOV感染的转录反应导致反差反应,这矛盾地导致致病
免疫反应和“免疫瘫痪”。为了解决这一假说,表观遗传和转录
在体外和体内感染EBOV期间的景观将被描述。一项全面的分析
由EBOV感染引起的转录组改变和表观遗传学改变将在两人中进行
从受感染的非人灵长类动物中分离出的原代细胞和特定类型的细胞。调查涉及
将进行编码转录因子的mRNAs的表达,以确定表观遗传的沉积
标记及其在基因激活和抑制中的作用,以及研究染色质的影响
使用人类供体细胞表达和分泌炎症介质的可及性。
该项目将以通过模拟EBOV感染而确定的关键转录节点为目标。中生成的数据
体外和体内,连同来自RP2和RP3的数据,将由生物信息学和
模型中的建模核心(核心D)。模型中确定的转录网络将预测关键的
代表漏洞的节点,将针对这些漏洞调整细胞响应并减少EBOV
发病机制。例如,染色质驻留酶和转录因子诱导表达
引起炎症和其他病理变化的基因将成为目标。
这项研究将导致对EBOV的表观遗传和转录反应的表征;到目前为止没有
对任何BSL-4级别病毒的表观遗传反应已经被表征。这项研究还将导致
开发针对宿主转录和表观遗传功能的治疗EBOV疾病的方法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Alexander Bukreyev其他文献
Alexander Bukreyev的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 42.55万 - 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:
$ 42.55万 - 项目类别:
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:
10602482 - 财政年份:2021
- 资助金额:
$ 42.55万 - 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:
$ 42.55万 - 项目类别:
相似国自然基金
基于ATAC-seq与DNA甲基化测序探究染色质可及性对莲两生态型地下茎适应性分化的作用机制
- 批准号:
- 批准年份:2024
- 资助金额:0.0 万元
- 项目类别:省市级项目
利用ATAC-seq联合RNA-seq分析TOP2A介导的HCC肿瘤细胞迁移侵
袭的机制研究
- 批准号:
- 批准年份:2024
- 资助金额:0.0 万元
- 项目类别:省市级项目
面向图神经网络ATAC-seq模体识别的最小间隔单细胞聚类研究
- 批准号:62302218
- 批准年份:2023
- 资助金额:30.00 万元
- 项目类别:青年科学基金项目
基于ATAC-seq策略挖掘穿心莲基因组中调控穿心莲内酯合成的增强子
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
基于单细胞ATAC-seq技术的C4光合调控分子机制研究
- 批准号:
- 批准年份:2021
- 资助金额:30 万元
- 项目类别:青年科学基金项目
基于ATAC-seq技术研究交叉反应物质197调控TFEB介导的自噬抑制子宫内膜异位症侵袭的分子机制
- 批准号:82001520
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
靶向治疗动态调控肺癌细胞DNA可接近性的ATAC-seq分析
- 批准号:81802809
- 批准年份:2018
- 资助金额:21.0 万元
- 项目类别:青年科学基金项目
运用ATAC-seq技术分析染色质可接近性对犏牛初级精母细胞基因表达的调控作用
- 批准号:31802046
- 批准年份:2018
- 资助金额:27.0 万元
- 项目类别:青年科学基金项目
基于ATAC-seq和RNA-seq研究CWIN调控采后番茄果实耐冷性作用机制
- 批准号:31801915
- 批准年份:2018
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
基于ATAC-seq高精度预测染色质相互作用的新方法和基于增强现实的3D基因组数据可视化
- 批准号:31871331
- 批准年份:2018
- 资助金额:59.0 万元
- 项目类别:面上项目
相似海外基金
Project #2 Integrated single-nucleus multi-omics (ATAC-seq+RNA-seq or chromatin accessibility + RNA-seq) of human TGs
项目
- 批准号:
10806548 - 财政年份:2023
- 资助金额:
$ 42.55万 - 项目类别:
A transposase system for integrative ChIP-exo and ATAC-seq analysis at single-cell resolution
用于单细胞分辨率综合 ChIP-exo 和 ATAC-seq 分析的转座酶系统
- 批准号:
10210424 - 财政年份:2018
- 资助金额:
$ 42.55万 - 项目类别:
EAPSI: Developing Single Nucleus ATAC-seq to Map the Ageing Epigenome
EAPSI:开发单核 ATAC-seq 来绘制衰老表观基因组图谱
- 批准号:
1714070 - 财政年份:2017
- 资助金额:
$ 42.55万 - 项目类别:
Fellowship Award
A cloud-based learning module to analyze ATAC-seq and single cell ATAC-seq data
基于云的学习模块,用于分析 ATAC-seq 和单细胞 ATAC-seq 数据
- 批准号:
10558379 - 财政年份:2001
- 资助金额:
$ 42.55万 - 项目类别: