Role and Regulation of MKP-1 in Sarcoidosis
MKP-1 在结节病中的作用和调节
基本信息
- 批准号:8438742
- 负责人:
- 金额:$ 38.97万
- 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:2013-01-18 至 2017-12-31
- 项目状态:已结题
- 来源:
- 关键词:3CH134 proteinATF2 geneAcuteAdrenal Cortex HormonesAffectAlveolar MacrophagesAttenuatedAutoimmunityBacteriaBindingBiologicalBronchoalveolar LavageCD14 geneCellsChronicClinicalDataDefectDetectionDiseaseDisease MarkerEtiologyExhibitsFailureFeedbackFrequenciesGenesGeneticGenetic TranscriptionGranulomaHealthHumanImmuneImmune responseImmunosuppressive AgentsInflammationInflammation MediatorsInflammatoryInflammatory ResponseLaboratoriesLeadLigandsMAPK14 geneMAPK8 geneMediatingMitogen Activated Protein Kinase 1Mitogen-Activated Protein KinasesModelingModificationNF-kappa BNatural ImmunityNewly DiagnosedNucleotidesOrganPathologyPathway interactionsPatientsPattern recognition receptorPeripheral Blood Mononuclear CellPharmaceutical PreparationsPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPlayPopulationProductionProtein DephosphorylationProtein phosphataseProteinsRegulationResolutionRoleSamplingSarcoidosisShapesSignal PathwaySignal TransductionSirolimusSpecificityStimulusStructureTLR4 geneTestingTherapeuticThreonineToll-like receptorsTranscriptTyrosineUniversitiesVariantWorkactivating transcription factoractivating transcription factor 1adaptive immunitycytokineinsightmRNA Stabilitymicrobialnovelpathogenphosphatase-1 kinasereceptorresponsetranscription factor
项目摘要
DESCRIPTION (provided by applicant): Numerous studies suggest that both environmental and genetic factors are involved in the immunopathogenic mechanisms underlying sarcoidosis. It has been postulated that microbial stimulation in a susceptible host plays a significant role in
this disease but no unifying pathogen has yet been identified. More importantly, the signaling pathways underlying chronic Th1-mediated pathology in sarcoidosis are unknown. Detection of uniquely conserved structures of bacteria occurs by specific host pattern-recognition receptors, such as the nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and Toll-like receptors (TLRs). Both receptors play a role in shaping innate and adaptive immunity. Upon microbial stimulation, TLRs and NLRs activate the transcription factor NF-kB and mitogen-activated protein kinase (MAPK) signaling cascades that regulate inflammatory genes and control both innate and adaptive immune responses. Among the three well defined MAPK pathways (JNK, ERK, and p38), p38 activation plays an essential role in induction of several inflammatory genes. Recently, we have shown that bronchoalveolar lavage (BAL) cells and alveolar macrophages (AMs) of sarcoid subjects exhibit constitutively active p38, but lack active ERK. Dual specificity phosphatase 1 (DUSP1), which is often referred to as MAP kinase phosphatase (MKP)-1, plays a central role in dephosphorylation and inhibition of active p38. Thus, lack of adequate negative regulation through MKP-1 may contribute to persistent inflammation in sarcoidosis. Our novel observation indicates that BAL cells and AMs from patients exhibit defective MKP-1 induction and sustained p38 phosphorylation with heightened inflammatory mediators in response to microbial stimulation. We hypothesize that the heightened inflammatory response in sarcoidosis is due, at least in part, to impaired negative feedback regulation of p38 as a result of MKP-1 (DUSP1) induction and a defective ERK activation in response to microbial stimulation. We further hypothesize that resolution of inflammation in response to corticosteroid therapy is dependent on induction and function of MKP-1. Additionally, we hypothesize that failure of MKP-1 induction is due to aberrant regulation of transcription factors required for MKP-1 transcription. We will test our hypothesis i three Specific Aims: 1- To test the hypothesis that defective ERK activation in response to microbial stimuli in sarcoidosis leads to failure of MKP-1 induction; 2- To determine the frequency of active p38 in patients with sarcoidosis in CD14+ AMs and to test the hypothesis that CD14+ peripheral blood mononuclear cells (PBMCs) parallel to p38 phenotype of AMs; and 3- To test the hypothesis that sarcoid AMs respond to microbial stimuli with aberrant expression or activity of transcription factors (TFs) involved in MKP-1 expression, and that effective drug treatment targets MKP-1 induction through modification of TFs.
描述(由申请人提供):大量研究表明,环境和遗传因素都参与了结节病的免疫病理机制。据推测,易感宿主中的微生物刺激在以下方面起重要作用:
这种疾病,但没有统一的病原体尚未确定。更重要的是,结节病中慢性Th 1介导的病理学的信号通路尚不清楚。细菌的独特保守结构的检测通过特异性宿主模式识别受体发生,例如核苷酸结合寡聚化结构域(NOD)样受体(NLR)和Toll样受体(TLR)。这两种受体在形成先天性和适应性免疫中发挥作用。在微生物刺激后,TLR和NLR激活转录因子NF-κ B和丝裂原活化蛋白激酶(MAPK)信号传导级联,其调节炎性基因并控制先天性和适应性免疫应答。在三种明确的MAPK通路(JNK、ERK和p38)中,p38活化在诱导几种炎症基因中起重要作用。最近,我们发现结节病患者的支气管肺泡灌洗(BAL)细胞和肺泡巨噬细胞(AM)表现出组成型活性p38,但缺乏活性ERK。双特异性磷酸酶1(DUSP 1),通常被称为MAP激酶磷酸酶(MKP)-1,在去磷酸化和抑制活性p38中发挥核心作用。因此,通过MKP-1缺乏足够的负调控可能有助于结节病的持续炎症。 我们的新观察表明,来自患者的BAL细胞和AM表现出有缺陷的MKP-1诱导和持续的p38磷酸化,以及对微生物刺激的反应中升高的炎症介质。我们推测结节病的炎症反应增强至少部分是由于MKP-1(DUSP 1)诱导导致的p38负反馈调节受损和微生物刺激导致的ERK激活缺陷。我们进一步假设皮质类固醇治疗后炎症的消退依赖于MKP-1的诱导和功能。此外,我们假设MKP-1诱导失败是由于MKP-1转录所需的转录因子的异常调节。我们将在三个具体目的中检验我们的假设:1-检验结节病中响应于微生物刺激的ERK激活缺陷导致MKP-1诱导失败的假设; 2-确定结节病患者CD 14 + AM中活性p38的频率,并检验CD 14+外周血单核细胞(PBMC)与AM的p38表型平行的假设;和3-检验以下假设:类肉瘤AM对微生物刺激物的应答具有参与MKP-1表达的转录因子(TF)的异常表达或活性,以及有效的药物治疗通过TF的修饰靶向MKP-1诱导。
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)
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Lobelia Samavati其他文献
Lobelia Samavati的其他文献
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{{ truncateString('Lobelia Samavati', 18)}}的其他基金
Diagnostic classifiers for sarcoidosis using a novel T7 phage display technology
使用新型 T7 噬菌体展示技术的结节病诊断分类器
- 批准号:
9805512 - 财政年份:2019
- 资助金额:
$ 38.97万 - 项目类别:
A novel T7 phage display technology to detect sarcoidosis specific antigens
新型T7噬菌体展示技术检测结节病特异性抗原
- 批准号:
10524024 - 财政年份:2019
- 资助金额:
$ 38.97万 - 项目类别:
A novel T7 phage display technology to detect sarcoidosis specific antigens
新型T7噬菌体展示技术检测结节病特异性抗原
- 批准号:
10320395 - 财政年份:2019
- 资助金额:
$ 38.97万 - 项目类别:
Role and Regulation of MKP-1 in Sarcoidosis
MKP-1 在结节病中的作用和调节
- 批准号:
8606501 - 财政年份:2013
- 资助金额:
$ 38.97万 - 项目类别:
Role and Regulation of MKP-1 in Sarcoidosis
MKP-1 在结节病中的作用和调节
- 批准号:
9196371 - 财政年份:2013
- 资助金额:
$ 38.97万 - 项目类别:
Development &validationof a panel of antibodies for the diagnosis of sarcoidosis
发展
- 批准号:
8392229 - 财政年份:2012
- 资助金额:
$ 38.97万 - 项目类别:
Development &validationof a panel of antibodies for the diagnosis of sarcoidosis
发展
- 批准号:
8243195 - 财政年份:2012
- 资助金额:
$ 38.97万 - 项目类别: