The Role of Arginine Methyltransferases in Interferon Signaling
精氨酸甲基转移酶在干扰素信号转导中的作用
基本信息
- 批准号:7882665
- 负责人:
- 金额:$ 37.52万
- 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:2008-09-15 至 2012-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAntimicrobial EffectAntiviral AgentsArginineAttenuatedAutoimmune DiseasesAutoimmune ProcessBindingBinding SitesCell NucleusCell ProliferationCellsComplexDNA BindingDevelopmentDimerizationDiseaseDrosophila genusEmbryoEventExhibitsFamilyFibroblastsGene TargetingGenesGeneticGenetic ScreeningGenetic TranscriptionGoalsHepatitis CHepatitis C virusHomologous GeneImmune responseIn VitroInfectionInterferon ReceptorInterferon Type IInterferonsKineticsLengthLigationLinkMalignant - descriptorMalignant NeoplasmsMediatingMethylationMolecularMultiple SclerosisMusNuclearNuclear ExportNuclear TranslocationPathologyPathway interactionsPhosphotransferasesPost-Translational Protein ProcessingPropertyProtein DephosphorylationProtein Tyrosine KinaseProtein Tyrosine PhosphataseProtein-Arginine N-MethyltransferaseRegulationRegulatory ElementRoleSignal PathwaySignal TransductionSiteSystemic Lupus ErythematosusTestingTyrosineTyrosine PhosphorylationViralVirus Diseasesarginine methyltransferasecytokinein vitro Assayinsightmembermetaplastic cell transformationpathogenpublic health relevancereceptorresponsesrc Homology Region 2 Domain
项目摘要
DESCRIPTION (provided by applicant): The cytokine Interferon (IFN) (/( mediates its antiviral, antiproliferative, and immunomodulatory effects through the engagement of the Jak/Stat signaling pathway. Ligation of the IFN(/( receptor results in activation of Jak tyrosine kinases and subsequent tyrosine phosphorylation of Stat1. Phosphorylated Stat1 either forms homodimers or heterodimerizes with Stat2 via reciprocal SH2 domain interactions. Dimerized Stats then translocate to the nucleus where they bind to regulatory elements in IFN response genes. In addition to tyrosine kinases, protein arginine methyltransferases (PRMT) have been implicated in IFN(/( signaling pathways through their physical association with members of the Jak/Stat pathway and through genetic studies. The Hepatitis C Virus interferes with IFN signaling by targeting arginine methylation of Stat1. We have now found that cells deficient in the Carm1 arginine methyltransferase exhibited elevated responses to IFN(-driven Stat1 activation, including a deficiency in Stat1 dephosphorylation and. Furthermore, Carm1 can methylate Stat1 in in vitro assays. Our HYPOTHESIS is that Carm1 negatively regulates Stat1 driven transcription by promoting the dephosphorylation of Stat1 by TCPTP. Specific Aims: 1) Define the intersection of Carm1 within IFN1/2 signaling pathways. We will examine Stat1 DNA binding, tetramerization, and association with target genes. We will also characterize the activity of Jak1, Tyk2, Stat1, Stat2, Stat3, and Stat5. 2) Determine the mechanism by which Carm1 regulates Stat1 dephosphorylation, including examining the importance of Carm1 catalytic activity and the effects on Carm1 on Stat1 interaction with Pias1 and TCPTP. The Stat1 methylation site will be determined. 3) Investigate the regulation of Carm1 by the IFN(/( signaling pathway, including expression, enzymatic activity, subcellular localization, and posttranslational modifications. Significance. These studies will provide insight into the mechanisms by which PRMTs regulate Type I IFN signaling, which may be altered during viral infection. PUBLIC HEALTH RELEVANCE: The interferon family of cytokines control pathogen infections through regulation of cellular proliferation and antiviral defenses, as well as through direct modulation of the immune response. For these reasons, the interferons are used clinically to treat viral and malignant diseases. Our project will address the molecular mechanisms of by which interferon signals are attenuated.
描述(由申请人提供):细胞因子干扰素(IFN)α通过参与Jak/Stat信号传导途径介导其抗病毒、抗增殖和免疫调节作用。IFN α受体的连接导致Jak酪氨酸激酶的活化和随后的Stat 1的酪氨酸磷酸化。磷酸化的Stat 1通过相互的SH 2结构域相互作用与Stat 2形成同源二聚体或异源二聚体。二聚化的Stats然后转移到细胞核,在那里它们与IFN应答基因中的调节元件结合。除酪氨酸激酶外,蛋白质精氨酸甲基转移酶(PRMT)通过与Jak/Stat途径成员的物理关联和通过遗传研究而与IFN α信号传导途径有关。丙型肝炎病毒通过靶向Stat 1的精氨酸甲基化干扰IFN信号传导。我们现在已经发现,缺乏Carm 1精氨酸甲基转移酶的细胞对IFN β驱动的Stat 1活化表现出更高的反应,包括Stat 1去磷酸化的缺陷和。此外,Carm 1可以在体外测定中甲基化Stat 1。我们的假设是Carm 1通过促进TCPTP对Stat 1的去磷酸化而负调控Stat 1驱动的转录。具体目的:1)确定Carm 1在IFN 1/2信号通路中的交叉点。我们将研究Stat 1 DNA结合,四聚体,并与靶基因的关联。我们还将表征Jak 1、Tyk 2、Stat 1、Stat 2、Stat 3和Stat 5的活性。2)确定Carm 1调节Stat 1去磷酸化的机制,包括检查Carm 1催化活性的重要性以及Carm 1对Stat 1与Pias 1和TCPTP相互作用的影响。将确定Stat 1甲基化位点。3)研究Carm 1通过IFN(/)信号通路的调节,包括表达、酶活性、亚细胞定位和翻译后修饰。意义这些研究将提供深入了解PRMT调节I型IFN信号传导的机制,该机制可能在病毒感染期间改变。公共卫生关系:细胞因子的干扰素家族通过调节细胞增殖和抗病毒防御以及通过直接调节免疫应答来控制病原体感染。由于这些原因,干扰素在临床上用于治疗病毒性和恶性疾病。我们的项目将解决干扰素信号减弱的分子机制。
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 }}
KERRI A MOWEN其他文献
KERRI A MOWEN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('KERRI A MOWEN', 18)}}的其他基金
Posttranscriptional regulation of TNFa by Carm1 in Macrophages
巨噬细胞中 Carm1 对 TNFa 的转录后调节
- 批准号:
8636332 - 财政年份:2013
- 资助金额:
$ 37.52万 - 项目类别:
Posttranscriptional regulation of TNFa by Carm1 in Macrophages
巨噬细胞中 Carm1 对 TNFa 的转录后调节
- 批准号:
8786493 - 财政年份:2013
- 资助金额:
$ 37.52万 - 项目类别:
An Activity-Based Assay to Screen for PRMT1 Inhibitors
基于活动的 PRMT1 抑制剂筛选试验
- 批准号:
8324861 - 财政年份:2012
- 资助金额:
$ 37.52万 - 项目类别:
PAD2: An Arginine Deiminase that Regulates Arthritis
PAD2:一种调节关节炎的精氨酸脱亚氨酶
- 批准号:
8282488 - 财政年份:2012
- 资助金额:
$ 37.52万 - 项目类别:
An Activity-Based Assay to Screen for PRMT1 Inhibitors
基于活动的 PRMT1 抑制剂筛选试验
- 批准号:
8460828 - 财政年份:2012
- 资助金额:
$ 37.52万 - 项目类别:
PAD2: An Arginine Deiminase that Regulates Arthritis
PAD2:一种调节关节炎的精氨酸脱亚氨酶
- 批准号:
8523780 - 财政年份:2012
- 资助金额:
$ 37.52万 - 项目类别:
Cytokine Gene Regulation by Modification of Arginine Residues
通过精氨酸残基修饰进行细胞因子基因调控
- 批准号:
8075289 - 财政年份:2010
- 资助金额:
$ 37.52万 - 项目类别:
CYTOKINE GENE REGULATION BY MODIFICATION OF ARGININE RESIDUES
通过精氨酸残基的修饰来调节细胞因子基因
- 批准号:
8171446 - 财政年份:2010
- 资助金额:
$ 37.52万 - 项目类别:
CYTOKINE GENE REGULATION BY MODIFICATION OF ARGININE RESIDUES
通过精氨酸残基的修饰来调节细胞因子基因
- 批准号:
7957844 - 财政年份:2009
- 资助金额:
$ 37.52万 - 项目类别:
The Role of Arginine Methyltransferases in Interferon Signaling
精氨酸甲基转移酶在干扰素信号转导中的作用
- 批准号:
7507284 - 财政年份:2008
- 资助金额:
$ 37.52万 - 项目类别:
相似海外基金
Development of soft denture liner with antimicrobial effect by using silver nanoparticles
利用银纳米粒子开发具有抗菌作用的软义齿衬垫
- 批准号:
15K20446 - 财政年份:2015
- 资助金额:
$ 37.52万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Antimicrobial effect of carvacrol against P. aeruginosa biofilms in a microfluidic chip
香芹酚对微流控芯片中铜绿假单胞菌生物膜的抗菌作用
- 批准号:
491168-2015 - 财政年份:2015
- 资助金额:
$ 37.52万 - 项目类别:
University Undergraduate Student Research Awards
Antimicrobial Effect of Nano-Rough Titanium Surfaces: Reduction of Microbial Adhesion and Mechanisms of Reduction
纳米粗糙钛表面的抗菌作用:微生物粘附的减少及其机制
- 批准号:
277895617 - 财政年份:2015
- 资助金额:
$ 37.52万 - 项目类别:
Research Grants
Antimicrobial effect of allograft and development of its preservation
同种异体移植物的抗菌作用及其保存研究进展
- 批准号:
24790129 - 财政年份:2012
- 资助金额:
$ 37.52万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Antimicrobial effect of a new class of light resistant silver(I) complexes Adhesi
新型耐光银(I)复合物Adhesi的抗菌作用
- 批准号:
8232775 - 财政年份:2012
- 资助金额:
$ 37.52万 - 项目类别:
Antimicrobial effect of a new class of light resistant silver(I) complexes Adhesi
新型耐光银(I)复合物Adhesi的抗菌作用
- 批准号:
8671602 - 财政年份:2012
- 资助金额:
$ 37.52万 - 项目类别:
ANTIMICROBIAL EFFECT OF PEROXIDASE IN LEUKOCYTES
过氧化物酶对白细胞的抗菌作用
- 批准号:
2058486 - 财政年份:1978
- 资助金额:
$ 37.52万 - 项目类别:
ANTIMICROBIAL EFFECT OF PEROXIDASE - ROLE IN LEUKOCYTES
过氧化物酶的抗菌作用 - 在白细胞中的作用
- 批准号:
3124386 - 财政年份:1978
- 资助金额:
$ 37.52万 - 项目类别:
ANTIMICROBIAL EFFECT OF PEROXIDASE IN LEUKOCYTES
过氧化物酶对白细胞的抗菌作用
- 批准号:
2058485 - 财政年份:1978
- 资助金额:
$ 37.52万 - 项目类别:
ANTIMICROBIAL EFFECT OF PEROXIDASE--ROLE IN LEUKOCYTES
过氧化物酶的抗菌作用——在白细胞中的作用
- 批准号:
3480438 - 财政年份:1978
- 资助金额:
$ 37.52万 - 项目类别: