Caspase-1 Activation by the Inflammasomes
炎症小体激活 Caspase-1
基本信息
- 批准号:10401755
- 负责人:
- 金额:$ 52.66万
- 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:2021-05-15 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:1-Phosphatidylinositol 4-KinaseAcidityAnti-Inflammatory AgentsArthritisAtherosclerosisBindingCASP1 geneCationsCell DeathCell VolumesChloridesCholesterolCrystallizationDataDevelopmentDiseaseGenerationsGeneticGoutHealthHomeostasisHumanInfectionInflammasomeInflammatoryInflammatory ResponseInnate Immune ResponseInterleukin-1 betaInterleukin-18IonsLaboratoriesLeadLigandsLightLysineMass Spectrum AnalysisMediatingMitosisMolecularMolecular ConformationMultiprotein ComplexesNIMANatural ImmunityNon-Insulin-Dependent Diabetes MellitusNucleotidesPathway interactionsPatternPhasePhosphorylationPhosphotransferasesPhysiologicalPost-Translational Protein ProcessingProcessProductionProtein DephosphorylationProteinsReceptor ActivationReceptor SignalingRegulationResearchRoleSignal PathwaySignal TransductionSilicon DioxideSiteStimulusTissuesToll-Like Receptor PathwayToll-like receptorsUbiquitinationUrateVirus Diseasescell injurycrystallinitycytokineexperimental studyin vivoinsightmacrophagemarenostrinmicrobialnovelnovel therapeuticspathogenpathogenic microbepathogenic virusphosphatidylinositol 4-phosphateprotein kinase Drecruitresponsestress granulesymportertherapeutic developmenttrans-Golgi Network
项目摘要
Inflammasomes are multi-protein complexes that assemble to activate caspase-1 in response to tissue damage
and infection by microbial or viral pathogens. Once activated, caspase-1 processes the inactive proforms of
interleukin-1β (IL-1β) and interleukin-18 (IL-18) to produce the active pro-inflammatory cytokines IL-1β and IL-
18, respectively. In addition, caspase-1 processes the gasdermin protein GSDMD to induce pyroptosis or
inflammatory cell death. The NLRP3 inflammasome is unique among the different inflammasomes in that it is
activated by diverse pathogen-associated and danger-associated molecular patterns (PAMPs and DAMPs)
derived from infection with microbial pathogens, or tissue damage. As a result, uncontrolled NLRP3 activation
can lead to a number of human inflammatory diseases, including gout, arthritis, atherosclerosis, and type 2
diabetes. The mechanism of NLRP3 activation by these seemingly unrelated stimuli is poorly understood but is
currently believed to require two distinct signals; a priming signal or “signal 1” produced by Toll-like receptors
(TLRs) and an activation signal or “signal 2” that induces fragmentation of trans Golgi network (TGN) and
binding to NEK7. Studies in the applicant's laboratory demonstrated that signal 1 induces post-translational
modification (PTM) of NLRP3 at critical sites via the MyD88 and TRIF signaling pathways and partial
oligomerization of NLRP3. In this application, studies are proposed to elucidate how TLR-induced PTM
contributes to posttranslational priming of the NLRP3 inflammasome by employing mass spectrometry to
identify and characterize all critical changes in the phosphorylation and other PTM profile of NLRP3 induced by
signal 1, and investigating how these changes contribute to activation of NLRP3. Additional aims will
investigate the effect of signal 1 and signal 1-induced PTM on NLRP3 association with dispersed TGN and
NEK7, and identify the TGN-associated kinases required for final assembly and activation of the
inflammasome. Finally, preliminary evidence suggest that kinases involved in the regulation of intracellular ion
homeostasis exert negative control on activation of NLRP3 by signal 2. Thus, additional experiments will
investigate how signaling from these kinases in macrophages impacts NEK7 phosphorylation and interaction
with NLRP3, and how genetic deficiency in these kinases impacts NLRP3-mediated pro-inflammatory responses
to PAMPs and DAMPs in vivo. Results from this research will provide fundamental new insights into the pathways
that regulate the assembly and activation of the NLRP3 inflammasome, and the cellular mechanisms that control
its activation. Successful completion of this study should have a high impact on the field by providing a unifying
paradigm for how NLRP3 can be regulated by an exceptionally diverse group of activating stimuli. Understanding
these mechanisms is of great scientific and health significance as this should better our understanding of the
molecular basis of NLRP3-related diseases and should in the long term help in the development of therapeutics
to alleviate these inflammatory diseases.
炎性小体是多蛋白复合物,其组装以响应组织损伤而激活caspase-1
以及微生物或病毒病原体的感染。一旦被激活,caspase-1处理非活性的前体,
白细胞介素-1 β(IL-1β)和白细胞介素-18(IL-18)产生活性促炎细胞因子IL-1β和IL-18。
18、分别此外,caspase-1加工gasdermin蛋白GSDMD以诱导细胞凋亡或
炎性细胞死亡NLRP 3炎性小体在不同炎性小体中是独特的,因为它是
由多种病原体相关和病原体相关分子模式(PAMP和DAMP)激活
来源于微生物病原体感染或组织损伤。结果,不受控制的NLRP 3激活
可导致许多人类炎症性疾病,包括痛风、关节炎、动脉粥样硬化和2型糖尿病。
糖尿病NLRP 3被这些看似无关的刺激激活的机制知之甚少,
目前认为需要两种不同的信号:由Toll样受体产生的启动信号或“信号1”
(TLR)和诱导反式高尔基体网络(TGN)片段化的激活信号或“信号2”,以及
与NEK 7结合。申请人实验室的研究表明,信号1诱导翻译后表达。
通过MyD 88和TRIF信号传导途径在关键位点修饰NLRP 3(PTM),
NLRP 3的寡聚化。在本申请中,提出了研究来阐明TLR诱导的PTM是如何发生的。
有助于NLRP 3炎性体的翻译后引发,
鉴定和表征由以下物质诱导的NLRP 3磷酸化和其他PTM谱的所有关键变化:
信号1,并研究这些变化如何有助于NLRP 3的激活。其他目标将
研究信号1和信号1诱导的PTM对NLRP 3与分散的TGN的关联的影响,
NEK 7,并确定TGN相关激酶的最终组装和激活所需的
炎性小体最后,初步证据表明,激酶参与调节细胞内离子
稳态通过信号2对NLRP 3激活施加负控制。因此,额外的实验将
研究巨噬细胞中这些激酶的信号传导如何影响NEK 7磷酸化和相互作用
以及这些激酶的遗传缺陷如何影响NLRP 3介导的促炎反应
PAMPs和DAMPs在体内。这项研究的结果将为这些途径提供基本的新见解,
调节NLRP 3炎性体的组装和激活,以及控制NLRP 3炎性体的细胞机制。
其激活。本研究的成功完成将通过提供统一的
NLRP 3是如何被一组异常多样的激活刺激调节的。理解
这些机制具有重要的科学和健康意义,因为这将使我们更好地了解
NLRP 3相关疾病的分子基础,并应在长期帮助治疗的发展
来缓解这些炎症性疾病。
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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Emad S Alnemri其他文献
Apoptosis in human monocytic THP.1 cells involves several distinct targets of N-tosyl-L-phenylalanyl chloromethyl ketone (TPCK)
人单核细胞 THP.1 细胞的凋亡涉及 N-甲苯磺酰-L-苯丙氨酰氯甲基酮(TPCK)的几个不同靶点
- DOI:
10.1038/sj.cdd.4400284 - 发表时间:
1997-10-01 - 期刊:
- 影响因子:15.400
- 作者:
Huijun Zhu;David Dinsdale;Emad S Alnemri;Gerald M Cohen - 通讯作者:
Gerald M Cohen
Emad S Alnemri的其他文献
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{{ truncateString('Emad S Alnemri', 18)}}的其他基金
Mechanisms of cell death in cutaneous melanoma
皮肤黑色素瘤细胞死亡的机制
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10316444 - 财政年份:2021
- 资助金额:
$ 52.66万 - 项目类别:
Mechanisms of cell death in cutaneous melanoma
皮肤黑色素瘤细胞死亡的机制
- 批准号:
10612054 - 财政年份:2021
- 资助金额:
$ 52.66万 - 项目类别:
Mechanisms of cell death in cutaneous melanoma
皮肤黑色素瘤细胞死亡的机制
- 批准号:
10428658 - 财政年份:2021
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$ 52.66万 - 项目类别:
Regulation of the Cell Death Program by DFNA5
DFNA5 对细胞死亡程序的调节
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10531607 - 财政年份:2019
- 资助金额:
$ 52.66万 - 项目类别:
Regulation of the Cell Death Program by DFNA5
DFNA5 对细胞死亡程序的调节
- 批准号:
10307533 - 财政年份:2019
- 资助金额:
$ 52.66万 - 项目类别:
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