STRUCTURAL AND FUNCTIONAL STUDIES OF THE TNF SIGNALING MACHINERIES
TNF 信号机械的结构和功能研究
基本信息
- 批准号:7721209
- 负责人:
- 金额:$ 4.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-05-15 至 2009-03-31
- 项目状态:已结题
- 来源:
- 关键词:BiochemicalBiologicalBiologyCell DeathCell SurvivalCellsCessation of lifeComplexComputer Retrieval of Information on Scientific Projects DatabaseDiseaseDissectionFundingGrantInstitutionLaboratory StudyMass Spectrum AnalysisMethodologyMethodsMolecularN-terminalPhaseProteinsProteolysisResearchResearch PersonnelResolutionResourcesRoentgen RaysRoleSignal TransductionSourceSpecificityStructureSystemTestingTumor Necrosis Factor ReceptorTumor Necrosis Factor-alphaTumor Necrosis FactorsUnited States National Institutes of HealthWorkX-Ray Crystallographybasecellular transductioncomputerized data processinghuman TNF proteinhuman diseaseinsightreconstitutionresearch study
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
Our laboratory studies the molecular mechanisms by which cells transduce and integrate environmental signals to influence the choices of cell fate such as survival, proliferation, differentiation and death. In particular, our work focuses on elucidating the molecular mechanisms of cell fate determination by the elaborate signaling machineries of the tumor necrosis factor (TNF) receptor superfamily, which are critical regulators of mammalian biology.
We begin by biochemical reconstitution and dissection of the signaling machineries to identify defined states of the assemblies and sub-assemblies. This is greatly aided by limited proteolysis followed by N-terminal sequencing and mass spectrometry analysis. Using X-ray crystallography to determine their detailed atomic structures is the primary methodology we use to reveal the molecular basis of signal transduction. Structure determination of isolated proteins and their complexes are performed by various phasing methods such as anomalous diffraction, ismorphous replacement and molecular replacement. Because of the advancement in rational incorporation of anomalous centers into protein crystals, anomalous diffraction is becoming the most important phasing method in our research. This method requires the high energy resolution and high flux X-ray beams as offered by undulator beam lines such as NE-CAT.
Structural insights are particularly important for complex systems such as this, in part because they provide the specificity required to determine unambiguously the role of a given interaction. Our aspiration is to use these structural perspectives to help unravel complex functional questions by testing structure-based hypotheses using cell biological experiments. Ultimately, by transforming static snapshots from our structural studies into an integrated understanding of the dynamic signaling process, we hope to understand the rules in this determination of cell survival and cell death. Because dysregulation of TNF signaling is associated with many human diseases, our studies will provide structural and functional platforms for understanding the genesis of these diseases.
这个子项目是许多利用
由NIH/NCRR资助的中心赠款提供的资源。子项目和
研究者(PI)可能从另一个NIH来源获得了主要资金,
因此可以在其他CRISP条目中表示。所列机构为
研究中心,而研究中心不一定是研究者所在的机构。
我们的实验室研究细胞吸收和整合环境信号以影响细胞命运选择的分子机制,如生存,增殖,分化和死亡。特别是,我们的工作重点是阐明细胞命运决定的分子机制的肿瘤坏死因子(TNF)受体超家族,这是哺乳动物生物学的关键调节器的精心制作的信号转导机制。
我们开始的生化重建和解剖的信号机制,以确定定义的状态的组件和子组件。这在很大程度上得益于有限的蛋白水解,然后进行N-末端测序和质谱分析。使用X射线晶体学来确定它们的详细原子结构是我们用来揭示信号转导的分子基础的主要方法。分离蛋白质及其复合物的结构测定可通过各种定相方法进行,如异常衍射、同晶置换和分子置换。由于在蛋白质晶体中合理引入反常中心的研究进展,反常衍射正成为我们研究中最重要的定相方法。这种方法需要高能量分辨率和高通量X射线束,如NE-CAT等波荡器束线所提供的。
结构洞察力对于像这样的复杂系统特别重要,部分原因是它们提供了明确确定给定相互作用的作用所需的特异性。我们的愿望是使用这些结构的角度来帮助解开复杂的功能问题,通过测试基于结构的假设,使用细胞生物学实验。最终,通过将我们结构研究的静态快照转化为对动态信号传导过程的综合理解,我们希望了解细胞存活和细胞死亡的决定规则。由于TNF信号的失调与许多人类疾病有关,我们的研究将为理解这些疾病的发生提供结构和功能平台。
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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Hao Wu其他文献
Hao Wu的其他文献
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{{ truncateString('Hao Wu', 18)}}的其他基金
Elucidating the functional mechanism of NLRP3 inflammasome activation
阐明NLRP3炎症小体激活的功能机制
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- 资助金额:
$ 4.24万 - 项目类别:
Project #2 Integrated single-nucleus multi-omics (ATAC-seq+RNA-seq or chromatin accessibility + RNA-seq) of human TGs
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10806548 - 财政年份:2023
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剖析复杂组织的表观转录组信号
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Elucidating the structural mechanism of pore formation by the (GSDM) Gasdermin family
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10417119 - 财政年份:2018
- 资助金额:
$ 4.24万 - 项目类别:
Elucidating the structural mechanism of pore formation by the (GSDM) Gasdermin family
阐明 (GSDM) Gasdermin 家族孔隙形成的结构机制
- 批准号:
10171760 - 财政年份:2018
- 资助金额:
$ 4.24万 - 项目类别:
Mechanistic Elucidation of Inflammasome Assembly and Regulation
炎症小体组装和调节的机制阐明
- 批准号:
9979736 - 财政年份:2016
- 资助金额:
$ 4.24万 - 项目类别:
NLRP1 and CARD8 Inflammasomes: Assembly, Regulation and Stress Sensing
NLRP1 和 CARD8 炎症小体:组装、调节和压力感应
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10391491 - 财政年份:2016
- 资助金额:
$ 4.24万 - 项目类别:
NLRP1 and CARD8 Inflammasomes: Assembly, Regulation and Stress Sensing
NLRP1 和 CARD8 炎症小体:组装、调节和压力感应
- 批准号:
10646160 - 财政年份:2016
- 资助金额:
$ 4.24万 - 项目类别:
Mechanistic Elucidation of Inflammasome Assembly and Regulation
炎症小体组装和调节的机制阐明
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9306767 - 财政年份:2016
- 资助金额:
$ 4.24万 - 项目类别:
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RAG重组酶在V(D)J重组和疾病中的分子机制
- 批准号:
9506691 - 财政年份:2016
- 资助金额:
$ 4.24万 - 项目类别:
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