Posttranscriptional regulation of TNFa by Carm1 in Macrophages
巨噬细胞中 Carm1 对 TNFa 的转录后调节
基本信息
- 批准号:8636332
- 负责人:
- 金额:$ 28.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-12-20 至 2015-11-30
- 项目状态:已结题
- 来源:
- 关键词:AnabolismApplications GrantsArginineAutoimmune ProcessBiogenesisBiological AssayBone MarrowCellsCollaborationsDataDrug IndustryEnzymesEquipment and supply inventoriesEventFamily memberGene ExpressionGene TargetingGenetic TranscriptionGenetic TranslationGoalsHistonesImmuneImmune responseInflammationInflammation MediatorsInflammatoryInhibitory Concentration 50LaboratoriesLettersLinkMalignant NeoplasmsMass Spectrum AnalysisMediatingMediator of activation proteinMessenger RNAMetabolic DiseasesMethylationModelingModificationMolecularMusNatural ImmunityNitrogenNuclear ExportNuclear Hormone ReceptorsPhagocytosisPhysiologicalPredispositionProcessProductionProtein-Arginine N-MethyltransferaseProteinsProteomeProteomicsPublishingRNARNA SplicingRegulationReportingResearch ProposalsRoleS-AdenosylmethionineSepsisSeptic ShockSerumStagingTLR4 geneTNF geneTherapeuticTranscription CoactivatorVaccinationarginine methyltransferasecell typechemokinecoactivator-associated arginine methyltransferase 1cytokinefollow-uphigh riskinhibitor/antagonistinnovationinterestmacrophagemethyl groupmutantneutrophilnovelpublic health relevanceresearch study
项目摘要
Macrophages are a central component of the innate immune response by the production of inflammatory
mediators, such as cytokines and chemokines, and by phagocytosis. The production of inflammatory cytokines
by macrophages has been linked to inflammatory, autoimmune, and even metabolic diseases. We find that the
protein arginine methyltransferase (PRMT) family member Carm1 is a negative regulator of TLR4 induced
TNF¿ biosynthesis in macrophages.! PRMTs catalyze the addition of a methyl group from S-
adenosylmethionine to guanidino nitrogen atoms on arginine residues. Carm1 has classically been described
as a transcriptional coactivator. We find that LPS-induced TNF¿ protein levels are increased in Carm1
deficient macrophages, whereas TNF¿ mRNA levels are equivalent, suggesting that Carm1 regulates TNF¿
production post-transcriptionally. In addition, mice bearing a deletion of Carm1 within the macrophage and
neutrophil lineages show enhanced susceptibility to the LPS-induced septic shock model, which correlates with
increased serum levels of TNF¿. Negative regulation of TNF¿ by Carm1 through posttranscriptional
mechanisms represents a novel mechanism for arginine methyltransferases in regulating innate immunity.
The goals of our studies are to identify the mechanism behind Carm1's regulation of TNF¿ biosynthesis.
We hypothesize that Carm1 negatively regulates the post-transcriptional processing of TNF¿. Our proposal
has two specific aims.
SPECIFIC AIM 1. To define the intersection of Carm1 with TNF¿ production.
We will examine the impact of Carm1 on TNF¿ mRNA splicing, nuclear export of TNF¿ mRNA, TNF¿
message stability, TNF¿ mRNA translation, and TNF¿ protein processing. In this Aim, we will pinpoint the
stage(s) of TNF¿ posttranscriptional regulation that intersects with Carm1. The results from this Aim will allow
us to focus in on Carm1 substrates from Aim 2 that most likely regulate TNF¿ production. Our TSRI colleague
and RNA regulation expert Jamie Williamson will provide guidance for this Aim (see attached letter).
SPECIFIC AIM 2. To build the CARM1-mediated proteomic landscape in macrophages.
To better understand the inhibitory role for Carm1 in regulating TNF¿ expression on a molecular level, we will
profile the arginine methylation proteome of Carm1 WT and Carm1 KO macrophages using mass
spectrometry. This Aim will be performed in collaboration with the TSRI Center for Physiological Proteomics
and Dr. Ben Cravatt's laboratory (see attached letter). This Aim will be essential to identify the mechanism by
which Carm1 regulates TNF¿ processing, follow-up studies for Aim 1.
!
巨噬细胞是先天免疫反应的核心组成部分,通过产生炎症
项目成果
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{{ 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:
8786493 - 财政年份:2013
- 资助金额:
$ 28.43万 - 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:
$ 28.43万 - 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:
$ 28.43万 - 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:
$ 28.43万 - 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:
$ 28.43万 - 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:
$ 28.43万 - 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:
$ 28.43万 - 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:
$ 28.43万 - 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:
7882665 - 财政年份:2008
- 资助金额:
$ 28.43万 - 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:
7686734 - 财政年份:2008
- 资助金额:
$ 28.43万 - 项目类别: