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:
    8606501
  • 负责人:
  • 金额:
    $ 37.44万
  • 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

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(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致病机制。据推测,在敏感宿主中,微生物刺激在 这种疾病但尚未鉴定出统一的病原体。更重要的是,在结节病中Th1介导的慢性病理的信号通路是未知的。细菌独特保守结构的检测是通过特定的宿主模式识别受体进行的,例如核苷酸结合的寡聚化结构域(NOD)样受体(NLRs)和Toll样受体(TLRs)。这两种受体都在塑造先天免疫和获得性免疫方面发挥作用。在微生物刺激下,TLRs和NLRs激活转录因子NF-kB和丝裂原活化蛋白激酶(MAPK)信号级联反应,调节炎症基因,控制先天和获得性免疫反应。在三条明确的MAPK通路(JNK、ERK和p38)中,p38的激活在几个炎症基因的诱导中起着至关重要的作用。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)表现出结构性活性的p38,但缺乏活性的ERK。双特异性磷酸酶1(DUSP1),通常被称为MKP-1,在去磷酸化和抑制活性p38的过程中起着核心作用。因此,通过MKP-1缺乏足够的负调控可能会导致结节病的持续性炎症。我们的新观察表明,患者的BAL细胞和AM在微生物刺激下表现出缺陷的MKP-1诱导和持续的p38磷酸化,并伴随着高水平的炎症介质。我们推测,结节病炎症反应的增强至少部分是由于MKP-1(DUSP1)诱导的p38负反馈调节受损和微生物刺激下ERK激活缺陷所致。我们进一步假设,激素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的诱导失败是由于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有三个具体目的:1-检验结节病中ERK激活缺陷导致MKP-1诱导失败的假说;2-确定CD14+AM中结节病患者激活p38的频率,并检验CD14+AM中CD14+外周血单个核细胞(PBMC)平行于AM p38表型的假设;3-检验结节样AM对微生物刺激的反应,参与MKP-1表达的转录因子(TFS)的异常表达或活性,以及有效的药物治疗通过修饰TFS来诱导MKP-1。

项目成果

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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:
    $ 37.44万
  • 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:
    $ 37.44万
  • 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:
    $ 37.44万
  • 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:
    8438742
  • 财政年份:
    2013
  • 资助金额:
    $ 37.44万
  • 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:
    $ 37.44万
  • 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:
    $ 37.44万
  • 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:
    $ 37.44万
  • 项目类别:
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