Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in rheumatoid arthritis

表征树突状细胞和巨噬细胞中的负信号传导以减轻类风湿性关节炎的炎症和骨质破坏

基本信息

  • 批准号:
    10321665
  • 负责人:
  • 金额:
    $ 33.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-15 至 2024-12-31
  • 项目状态:
    已结题

项目摘要

The goal of this proposal is to understand the mechanisms underlying how negative endogenous signaling reduces chronic inflammation in rheumatoid arthritis (RA), which can provide novel therapeutic targets for diseases related to inflammation and tissue destruction. Current therapies for RA have serious negative effects on the patients’ immune system, and can cause malignancies, pneumonia, and tuberculosis. Positive regulators of inflammation in RA (such as NF-κB) have been well characterized, however, the negative endogenous regulators of RA-induced inflammation and bone destruction, especially in macrophages and dendritic cells in RA pathological condition remain elusive. The proposed study will characterize the negative endogenous regulators of differentiation and activity in macrophages and dendritic cells (DCs) that attenuate RA-induced inflammation and tissue destruction. We noted that Gα13 deficiency in macrophages or dendritic cells aggravated inflammation in mouse RA model. AAV mediated overexpression of local Gna13 constitutively active form (Gna13CA) not only significantly reduced bone destruction, but also dramatically inhibited inflammation in RA, indicating that Gna13CA could protect against inflammation in a mouse model of RA. Our RNA sequencing (RNA-seq) analysis showed that Gα13 may negatively regulate macrophage and DC differentiation and activation and ChIP sequencing (ChIP-seq) analysis showed the enrichment of NF-κB motif site binding on the genome-wide promoters of the genes related to inflammation in Gα13 deficient macrophages with TNFα or LPS stimulations. Our preliminary data showed that Gα13 deficiency promotes Akt activity, STAT3 phosphorylation and NF-κB signaling pathway activation in dendritic cells and macrophages. Based on our preliminary studies, we hypothesize that Gα13 is a master negative regulator that attenuates inflammation and bone destruction associated with rheumatoid arthritis through the Gα13/RhoA/AKT/IKK/NF-κB pathway in macrophages and dendritic cells. Three specific aims are proposed to test our hypothesis. In Aim 1, we will determine the role of Gα13 in inflammation and bone destruction in rheumatoid arthritis (RA) by characterizing the phenotypes and pathomechanism of conditional knockout (CKO) mouse models via loss-of-function approach in RA. In Aim 2, we will define the roles and therapeutic effects of Gα13CA in inflammation and bone destruction in RA by characterizing the phenotypes and pathomechanism of conditional transgenic overexpression (OE) mouse models via gain-of-function approach in RA. We will characterize the molecular mechanism by which Gα13 regulates inflammation and bone destruction in RA through Gα13/ RhoA/AKT/IKK/NF-κB signaling, STAT3 signaling, and TLRs signaling pathways in macrophages and dendritic cells in Aim 3. The proposed study will provide important insights into the negative regulation of the cells of the immune system to effectively target inflammation and bone destruction in RA. Knowledge gained from this study may bring forth potential superior therapeutic means for treating RA and other inflammatory bone diseases.
这项建议的目标是了解内源性负面信号的潜在机制。 减少类风湿性关节炎(RA)的慢性炎症,可为 与炎症和组织破坏有关的疾病。目前治疗类风湿性关节炎的方法有严重的负面影响 会影响患者的免疫系统,并可能导致恶性肿瘤、肺炎和肺结核。积极的监管机构 类风湿性关节炎(如核因子-κB)的炎症反应已有很好的特征,然而,内源性的负性 RA诱导的炎症和骨破坏的调节,特别是在巨噬细胞和树突状细胞 RA的病理状况仍然难以捉摸。拟议的研究将描述负面的内生性 巨噬细胞和树突状细胞(DC)的分化和活性调节因子可减弱RA诱导 炎症和组织破坏。我们注意到巨噬细胞或树突状细胞中Gα13缺乏 加重小鼠RA模型的炎症反应。AAV介导的局部GNA13结构性过表达 活性形式(Gna 13CA)不仅显著减少骨破坏,而且显著抑制 在类风湿关节炎小鼠模型中,Gna 13CA对炎症有保护作用。我们的 核糖核酸序列分析表明,Gα13对巨噬细胞和DC具有负性调节作用 分化活化和芯片测序(CHIP-SEQ)分析表明,NF-κB基序丰富 G-α-13缺陷巨噬细胞炎症相关基因全基因组启动子的位点结合 用肿瘤坏死因子、α或脂多糖刺激。我们的初步数据显示,Gα13缺乏促进Akt活性,STAT3 树突状细胞和巨噬细胞中的磷酸化和NF-κB信号通路激活。基于 我们的初步研究,我们假设Gα13是一种主要的负性调节因子,可以减轻炎症 并通过Gα13/RhoA/AKT/IKK/NF-κB途径与类风湿关节炎相关的骨破坏 巨噬细胞和树突状细胞。为了检验我们的假设,本文提出了三个具体目标。在目标1中,我们将 确定Gα13在类风湿关节炎(RA)炎症和骨破坏中的作用 条件性基因敲除(CKO)小鼠功能丧失模型的表型及发病机制 在类风湿性关节炎中的方法。在目标2中,我们将确定Gα13CA在炎症和骨骼中的作用和治疗作用 条件转基因的表型特征和致病机制对RA的破坏作用 在类风湿关节炎中通过功能获得法建立过度表达(OE)小鼠模型。我们将描述分子的特征 G-α-13通过G-α-13调节RA炎症和骨破坏的机制 巨噬细胞和树突状细胞中的RhoA/AKT/IKK/NF-κB信号、STAT3信号和TLR信号通路 AIM 3中的细胞。这项拟议的研究将为研究AIM中细胞的负调控提供重要的见解 免疫系统有效地针对类风湿性关节炎的炎症和骨破坏。从这项研究中获得的知识 可能为治疗类风湿性关节炎等炎症性骨病提供潜在的更好的治疗手段。

项目成果

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YI-PING LI其他文献

YI-PING LI的其他文献

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{{ truncateString('YI-PING LI', 18)}}的其他基金

G13 signaling attenuates periodontal inflammation and alveolar bone loss in the mouse model of age-associated periodontitis
G13 信号传导可减轻年龄相关性牙周炎小鼠模型中的牙周炎症和牙槽骨丢失
  • 批准号:
    10404267
  • 财政年份:
    2021
  • 资助金额:
    $ 33.11万
  • 项目类别:
Inhibiting inflammation and bone erosion in periodontal disease by targeting cell endogenous negative signaling
通过靶向细胞内源性负信号传导抑制牙周病中的炎症和骨侵蚀
  • 批准号:
    10405318
  • 财政年份:
    2021
  • 资助金额:
    $ 33.11万
  • 项目类别:
Mechanism of chemotherapy potentiation of muscle wasting in cancer cachexia
化疗增强癌症恶病质肌肉萎缩的机制
  • 批准号:
    10362568
  • 财政年份:
    2021
  • 资助金额:
    $ 33.11万
  • 项目类别:
G13 signaling attenuates periodontal inflammation and alveolar bone loss in the mouse model of age-associated periodontitis
G13 信号传导可减轻年龄相关性牙周炎小鼠模型中的牙周炎症和牙槽骨丢失
  • 批准号:
    10444932
  • 财政年份:
    2021
  • 资助金额:
    $ 33.11万
  • 项目类别:
Inhibiting inflammation and bone erosion in periodontal disease by targeting cell endogenous negative signaling
通过靶向细胞内源性负信号传导抑制牙周病中的炎症和骨侵蚀
  • 批准号:
    10327686
  • 财政年份:
    2021
  • 资助金额:
    $ 33.11万
  • 项目类别:
Inhibiting inflammation and bone erosion in periodontal disease by targeting cell endogenous negative signaling
通过靶向细胞内源性负信号传导抑制牙周病中的炎症和骨侵蚀
  • 批准号:
    10559645
  • 财政年份:
    2021
  • 资助金额:
    $ 33.11万
  • 项目类别:
Mechanism of chemotherapy potentiation of muscle wasting in cancer cachexia
化疗增强癌症恶病质肌肉萎缩的机制
  • 批准号:
    10550259
  • 财政年份:
    2021
  • 资助金额:
    $ 33.11万
  • 项目类别:
Targeting circulating HSP70 and HSP90 for the treatment of cancer cachexia
靶向循环 HSP70 和 HSP90 治疗癌症恶病质
  • 批准号:
    10212970
  • 财政年份:
    2020
  • 资助金额:
    $ 33.11万
  • 项目类别:
Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in rheumatoid arthritis
表征树突状细胞和巨噬细胞中的负信号传导以减轻类风湿性关节炎的炎症和骨质破坏
  • 批准号:
    10616608
  • 财政年份:
    2020
  • 资助金额:
    $ 33.11万
  • 项目类别:
Characterizing the negative signaling in dendritic cells and macrophages to attenuate inflammation and bone destruction in rheumatoid arthritis
表征树突状细胞和巨噬细胞中的负信号传导以减轻类风湿性关节炎的炎症和骨质破坏
  • 批准号:
    10405848
  • 财政年份:
    2020
  • 资助金额:
    $ 33.11万
  • 项目类别:

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