Role and Mitigation of Inflammasomes and Inflammation During COVID-19
COVID-19 期间炎症小体和炎症的作用和缓解
基本信息
- 批准号:10470451
- 负责人:
- 金额:$ 76.82万
- 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:2021-09-01 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAddressAdult Respiratory Distress SyndromeAlveolarAnti-Inflammatory AgentsApoptosisAttenuatedBioavailableBiologicalCASP1 geneCOVID-19COVID-19 pandemicCOVID-19 patientCOVID-19/ARDSCell DeathCellsCessation of lifeCleaved cellClinical TrialsComplexCoronavirusDangerousnessDataDatabasesDeteriorationGene DeletionGenesHumanIn VitroInfectionInflammasomeInflammationInflammatoryInflammatory ResponseInterleukin-1Interleukin-1 ReceptorsInterleukin-1 betaInterleukin-18Interleukin-6IrrigationLeadLungMediatingMolecularMouse StrainsMusOralOutcomePathway interactionsPatientsPatternPeripheral Blood Mononuclear CellPlayProcessProductionProteinsPulmonary PathologyRoleSARS coronavirusSARS-CoV-2 infectionSevere Acute Respiratory SyndromeSeveritiesSpecimenStromal CellsStructureSystemTNF geneTestingTherapeuticViral ProteinsVirusanakinracell injurycomparative efficacycytokinecytokine release syndromedesignefficacy testinghumanized mousein vivoinhibitor/antagonistinterleukin-1beta-converting enzyme inhibitormembermicrobialmicrobiota metabolitesnovelnovel strategiespathogenprotein complexreceptorresponsesensorstandard caresuccesstherapeutic targettherapeutically effectivetranscriptome
项目摘要
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 has resulted in swift and catastrophic losses
of human lives globally. Acute respiratory distress syndrome (ARDS) is one of the most
detrimental outcomes of COVID-19 infection that can lead to the rapid deterioration and death of
patients. ARDS is primarily caused by the cytokine storm which unleashes a plethora of
inflammatory cytokines during the late stages of COVID-19. The master cytokines that are
thought to be responsible for much of the damage are interleukin 1 (IL-1), interleukin 6 (IL-6)
and tumor necrosis factor (TNF). Currently several clinical trials have already been initiated to
test the efficacy of biologic inhibitors to target these pathways. However, in many cases, the
mechanism and impact of these cytokines during ARDS are poorly understood. An indepth
mechanistic understanding of cytokine induction is important because this understanding will
significantly impact the design and success of ARDS treatment. This application focuses on the
role and mitigation of the inflammasome complex which leads to the proinflammatory cytokine,
IL-1β, in ARDS. The inflammasome is a protein supramolecular structure that leads to caspase
1 activation, which then cleaves pro-IL-1β and pro-IL-18 to mature IL-1β and IL-18. In addition to
the release of IL-1β and IL-18, caspase 1 cleaves gasdermin D to cause inflammatory pyroptotic
cell death, thus leading to a cascade of cell death and inflammation. The inflammasome is
comprised of a receptor or sensor, with the most prominent ones represented by NLRP1,
NLRP3, NLRP6, NLRC4 and AIM2. It also includes an adaptor molecule ASC (apoptosis-
associated speck-like protein containing a CARD), and the effector caspase-1. Each receptor
or sensor can be activated by specific pathogen products called PAMPs or cell damage
associated molecules called DAMPs. NLRP3 is the most studied member since it is activated by
a large list of stimulators. Studies of other coronavirus such as SARS show inflammasome
activation by key viral proteins. Expression data from COVID-19 patients also show dramatic
increases of inflammasome sensors in the bronchial alveolar lavage of COVID-19 patients.
However the mechanism of inflammasome activation by SARS-CoV-2, especially in the human
system, remains unknown. This proposal will identify the viral protein that activates human
inflammasome, and further define the specific human inflammasome sensor/receptor that
mediates the response. We will then design ways to reduce inflammasome activation during
SARS-CoV-2 infection using established therapeutics as well as new approaches to broadly
attenuate inflammatory cytokines.
摘要
由SARS-CoV-2引发的新冠肺炎大流行造成了迅速而灾难性的损失
在全球范围内对人类生命的影响。急性呼吸窘迫综合征(ARDS)是最常见的
新冠肺炎感染的有害后果,可导致心脏迅速恶化和死亡
病人。ARDS主要是由细胞因子风暴引起的,这种风暴释放了过多的
新冠肺炎晚期炎性细胞因子的变化。主要的细胞因子是
被认为对大部分损害负有责任的是白介素1(IL-1)、白介素6(IL-6)
和肿瘤坏死因子(TNF)。目前已经启动了几项临床试验,以
测试生物抑制剂的有效性,以针对这些途径。然而,在许多情况下,
这些细胞因子在ARDS中的作用机制和影响目前还知之甚少。深度
对细胞因子诱导的机械理解是重要的,因为这种理解将
显著影响ARDS治疗的设计和成功。此应用程序侧重于
炎症体复合体的作用和缓解,导致促炎细胞因子,
IL-1β,急性呼吸窘迫综合征。炎症体是一种导致caspase的蛋白质超分子结构。
1激活,然后将前IL-1β和前IL-18切割成成熟的IL-1β和IL-18。除了……之外
IL-1β和IL-18、Caspase 1裂解G asdermin D致炎性焦虑症
细胞死亡,从而导致细胞死亡和炎症的级联反应。发炎的是
由受体或传感器组成,其中最突出的由NLRP1代表,
NLRP3、NLRP6、NLRC4和AIM2。它还包括一个接头分子ASC(细胞凋亡-
含有卡片的相关斑点样蛋白),以及效应器caspase-1。每个受体
或传感器可被称为PAMPs或细胞损伤的特定病原体产物激活
被称为阻尼剂的相关分子。NLRP3是研究最多的成员,因为它被激活
一大串刺激物。对SARS等其他冠状病毒的研究显示炎症体
关键病毒蛋白的激活。来自新冠肺炎患者的表情数据也显示出戏剧性的
新冠肺炎患者支气管肺泡灌洗液中炎性小体感受器增加。
然而,SARS-CoV-2激活炎症小体的机制,特别是在人类中
系统,仍然是未知的。这项提议将确定激活人类的病毒蛋白
炎症体,并进一步定义特定的人类炎症体传感器/受体,
调停反应。然后我们将设计方法来减少炎性小体的激活
使用现有疗法和新方法广泛应用于SARS-CoV-2感染
减弱炎性细胞因子。
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)
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Beverly H Koller其他文献
The hippocratic finger points the blame at PGE2
希波克拉底的手指指向 PGE2 应受责备。
- DOI:
10.1038/ng0608-691 - 发表时间:
2008-06-01 - 期刊:
- 影响因子:29.000
- 作者:
Kenneth G Coggins;Thomas M Coffman;Beverly H Koller - 通讯作者:
Beverly H Koller
Beverly H Koller的其他文献
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{{ truncateString('Beverly H Koller', 18)}}的其他基金
Role and Mitigation of Inflammasomes and Inflammation During COVID-19
COVID-19 期间炎症小体和炎症的作用和缓解
- 批准号:
10521963 - 财政年份:2022
- 资助金额:
$ 76.82万 - 项目类别:
Modeling the contribution of coronavirus cellular tropism to viral pathogenesis
模拟冠状病毒细胞向性对病毒发病机制的贡献
- 批准号:
10583101 - 财政年份:2022
- 资助金额:
$ 76.82万 - 项目类别:
Role and Mitigation of Inflammasomes and Inflammation During COVID-19
COVID-19 期间炎症小体和炎症的作用和缓解
- 批准号:
10666572 - 财政年份:2022
- 资助金额:
$ 76.82万 - 项目类别:
Mouse models for study of the NLRP1 and CARD8 inflammasomes
用于研究 NLRP1 和 CARD8 炎性体的小鼠模型
- 批准号:
10354472 - 财政年份:2021
- 资助金额:
$ 76.82万 - 项目类别:
Mouse models for study of the NLRP1 and CARD8 inflammasomes
用于研究 NLRP1 和 CARD8 炎性体的小鼠模型
- 批准号:
10493370 - 财政年份:2021
- 资助金额:
$ 76.82万 - 项目类别:
Genetically humanized mice for modeling human Fc-receptor interaction during influenza infection
用于模拟流感感染期间人类 Fc 受体相互作用的基因人源化小鼠
- 批准号:
10117188 - 财政年份:2020
- 资助金额:
$ 76.82万 - 项目类别:
Assembly of disease-relevant pathways in the mouse
小鼠疾病相关通路的组装
- 批准号:
8638644 - 财政年份:2014
- 资助金额:
$ 76.82万 - 项目类别:
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