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引起的COVID-19大流行导致了迅速和灾难性的损失
全球人类生活的一部分。急性呼吸窘迫综合征(ARDS)是目前世界上最常见的
COVID-19感染的有害后果,可能导致患者的迅速恶化和死亡,
患者急性呼吸窘迫综合征主要是由细胞因子风暴引起的,
COVID-19晚期的炎症细胞因子。主要的细胞因子
被认为是造成大部分损伤的原因是白细胞介素1(IL-1),白细胞介素6(IL-6),
和肿瘤坏死因子(TNF)。目前已经启动了几项临床试验,
测试生物抑制剂针对这些途径的功效。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尚不清楚。深入的
对细胞因子诱导机制的理解是重要的,因为这种理解将
严重影响ARDS治疗的设计和成功。本申请集中于
导致促炎细胞因子的炎性体复合物的作用和减轻,
IL-1β,在ARDS中。炎性小体是一种蛋白质超分子结构,导致半胱天冬酶
1活化,然后切割pro-IL-1β和pro-IL-18以使IL-1β和IL-18成熟。除了
IL-1β和IL-18的释放,半胱天冬酶1切割gasdermin D,引起炎性热原
细胞死亡,从而导致细胞死亡和炎症级联。炎性小体是
由受体或传感器组成,其中最突出的由NLRP 1代表,
NLRP 3、NLRP 6、NLRC 4和AIM 2。它还包括一个衔接分子ASC(凋亡-
相关的含有CARD的斑点样蛋白)和效应物半胱天冬酶-1。每个受体
或传感器可以被称为PAMP的特定病原体产物或细胞损伤激活
称为DAMPs的相关分子。NLRP 3是研究最多的成员,因为它被激活,
一大堆刺激物对其他冠状病毒如SARS的研究表明,
关键病毒蛋白的激活。来自COVID-19患者的表达数据也显示了显着的
COVID-19患者支气管肺泡灌洗中炎性小体传感器的增加。
然而,SARS-CoV-2激活炎性小体的机制,特别是在人类中,
系统,仍然未知。该提案将识别激活人类的病毒蛋白
本发明还涉及特异性人炎性体传感器/受体,其
调解回应。然后,我们将设计方法,以减少炎性小体激活,
SARS-CoV-2感染使用已建立的治疗方法以及新的方法,以广泛
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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