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.
本提案的目的是了解负内源性信号如何产生的机制

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)
专利数量(0)

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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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