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
• 负责人: Lobelia Samavati
• 金额: $ 37.44万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8606501
• 关键词: 3CH134 protein; ATF2 gene; Acute; Adrenal Cortex Hormones; Affect; Alveolar Macrophages; Attenuated; Autoimmunity; Bacteria; Binding; Biological; Bronchoalveolar Lavage; CD14 gene; Cells; Chronic; Clinical; Data; Defect; Detection; Disease; Disease Marker; Etiology; Exhibits; Failure; Feedback; Frequencies; Genes; Genetic; Genetic Transcription; Granuloma; Health; Human; Immune; Immune response; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Laboratories; Lead; Ligands; MAPK14 gene; MAPK8 gene; Mediating; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Modeling; Modification; NF-kappa B; Natural Immunity; Newly Diagnosed; Nucleotides; Organ; Pathology; Pathway interactions; Patients; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Population; Production; Protein Dephosphorylation; Protein phosphatase; Proteins; Regulation; Resolution; Role; Sampling; Sarcoidosis; Shapes; Signal Pathway; Signal Transduction; Sirolimus; Specificity; Stimulus; Structure; TLR4 gene; Testing; Therapeutic; Threonine; Toll-like receptors; Transcript; Tyrosine; Universities; Variant; Work; activating transcription factor; activating transcription factor 1; adaptive immunity; cytokine; insight; mRNA Stability; microbial; novel; pathogen; phosphatase-1 kinase; receptor; response; transcription factor; 3CH134 protein; ATF2 gene; Acute; Adrenal Cortex Hormones; Affect; Alveolar Macrophages; Attenuated; Autoimmunity; Bacteria; Binding; Biological; Bronchoalveolar Lavage; CD14 gene; Cells; Chronic; Clinical; Data; Defect; Detection; Disease; Disease Marker; Etiology; Exhibits; Failure; Feedback; Frequencies; Genes; Genetic; Genetic Transcription; Granuloma; Health; Human; Immune; Immune response; Immunosuppressive Agents; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Laboratories; Lead; Ligands; MAPK14 gene; MAPK8 gene; Mediating; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Modeling; Modification; NF-kappa B; Natural Immunity; Newly Diagnosed; Nucleotides; Organ; Pathology; Pathway interactions; Patients; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Population; Production; Protein Dephosphorylation; Protein phosphatase; Proteins; Regulation; Resolution; Role; Sampling; Sarcoidosis; Shapes; Signal Pathway; Signal Transduction; Sirolimus; Specificity; Stimulus; Structure; TLR4 gene; Testing; Therapeutic; Threonine; Toll-like receptors; Transcript; Tyrosine; Universities; Variant; Work; activating transcription factor; activating transcription factor 1; adaptive immunity; cytokine; insight; mRNA Stability; microbial; novel; pathogen; phosphatase-1 kinase; receptor; response; transcription factor

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发病机制。据推测，易感宿主中的微生物刺激在 该疾病尚未确定，但尚未发现统一的病原体。更重要的是，结节病中的慢性Th1介导的病理学的信号传导途径尚不清楚。特定的宿主模式识别受体（例如核苷酸结合寡聚结构域（NOD）样受体（NLR）和Toll-like受体（TLR），发现了独特保守的细菌结构。两种受体在塑造先天和适应性免疫方面都起着作用。在微生物刺激下，TLR和NLR激活转录因子NF-KB和有丝分裂原激活的蛋白激酶（MAPK）信号传导级联，这些蛋白质级联反应并控制先天性和适应性免疫反应。在三个良好定义的MAPK途径（JNK，ERK和P38）中，p38激活在诱导几种炎症基因中起着至关重要的作用。最近，我们已经表明，肌肉腔灌洗（BAL）细胞和肺泡受试者的肺泡巨噬细胞（AMS）表现出组成型活性p38，但缺乏活性ERK。双重特异性磷酸酶1（DUSP1）通常称为MAP激酶磷酸酶（MKP）-1，在非磷酸化和抑制活性p38中起着核心作用。因此，缺乏通过MKP-1的足够的负调控可能导致结节病的持续炎症。 我们的新观察结果表明，来自患者的BAL细胞和AMS表现出有缺陷的MKP-1诱导，并持续p38磷酸化，炎症介质对微生物刺激的响应增强。我们假设结节病中的炎症反应的增强至少部分是由于MKP-1（DUSP1）诱导导致p38的负反馈调节，并且响应微生物刺激而导致ERK激活有缺陷。我们进一步假设响应皮质类固醇治疗的炎症解决取决于MKP-1的诱导和功能。此外，我们假设MKP-1诱导的失败是由于对MKP-1转录所需的转录因子的异常调节所致。我们将检验我们的假设I三个特定目的：1-检验以下假设：响应于结节病中微生物刺激的ERK激活导致MKP-1诱导失败； 2-确定CD14+ AM中结节症患者的活动p38的频率，并测试CD14+外周血单核细胞（PBMC）与AMS p38表型平行的假设； 3-检验了susoid AMs对MKP-1表达涉及的转录因子（TFS）的异常表达或活性的微生物刺激的假设，并且有效的药物治疗方法通过修饰TFS来诱导MKP-1诱导。