miR-21 regulation of autoreactive B cell and lupus nephritis development

miR-21对自身反应性B细胞和狼疮性肾炎发展的调节

基本信息

  • 批准号:
    10888833
  • 负责人:
  • 金额:
    $ 54.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-18 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

Project Summary MicroRNAs (miRNAs) are critical post-transcriptional regulators of gene expression in immunity and autoimmunity, although many miRNAs remain poorly characterized. One such miRNA, miRNA-21 (miR-21), is upregulated in systemic lupus erythematosus (SLE) patients and promotes various diseases in mouse models. These include experimental autoimmune encephalomyelitis (EAE), asthma, cancer, and our findings on its role in toll-like receptor 7 (TLR7)-driven SLE in mice. We found that TLR7 overexpressing SLE-prone B6.Sle1bYaa mice deficient in miR-21 (Sle1bYaamiR-21-/-) had reduced germinal center (GC) B cell, T follicular helper (Tfh) cell and plasma cell (PC) responses. These responses in Sle1bYaamiR-21-/- mice were strongly associated with reduced autoantibody, and splenic and bone marrow autoantibody-producing antibody forming cell (AFC) responses. These data substantiate a role for miR-21 in the loss of B cell tolerance and autoimmunity, which necessitates identification of mechanisms (focus of the grant) by which miR-21 promotes autoantibody production and SLE. This will fill gaps in knowledge and may help discover an urgently needed targeted therapy for SLE, a debilitating disease that affects millions of Americans and people world-wide. TLR signaling, especially TLR7, promotes SLE in humans and murine models, and an attractive therapeutic target. TLR7 signaling activates the NF-kB inflammatory signaling pathway. TLR7 upregulates miR-21 expression in B cells which can target the negative regulator of NF-kB signaling, Peli1, although the role of miR-21 in regulating NF- kB signaling in SLE-prone B cells by targeting Peli1 is unknown. Preliminary data showed that B cells from Sle1bYaamiR-21-/- mice have increased Peli1 expression compared to control Sle1bYaa B cells. In addition, previous studies implicated TLR signaling in metabolic reprogramming, primarily through the activation of the PI3K/Akt/mTOR pathway in various immune conditions, although the role of this pathway in TLR7-mediated metabolic reprograming in B cells in SLE is not clear. miR-21 was also shown to regulate the PI3K/Akt/mTOR pathway in various models; however, its role in regulating B cell metabolism in TLR7-driven SLE is not known. Interestingly, our RNA-seq analysis of B cells from a TLR7-induced model showed negatively enriched genes in the PI3K/Akt/mTOR pathway in the absence of miR-21. Additional preliminary data showed increased extracellular acidification (ECAR) and oxygen consumption (OCR) rates in Sle1bYaa B cells overexpressing TLR7 compared to Sle1b B cells, indicating a more energetic phenotype in response to TLR7 signaling. Conversely, Sle1bYaamiR-21-/- B cells exhibited reduced ECAR and OCR compared to Sle1bYaa B cells. We hypothesize that miR-21 promotes TLR7-driven systemic autoimmune responses and SLE disease by regulating TLR7-NF-kB signaling and metabolic reprogramming in B cells. Proposed hypothesis and specific aims will help delineate the mechanism by which miR-21 drives autoimmune responses and lupus nephritis and will inform us whether miR-21 or miR-21 regulated pathway(s) can be a therapeutic target for SLE.
项目摘要 微小RNA(miRNAs)是免疫中基因表达的关键转录后调节因子, 自身免疫,尽管许多miRNAs仍然缺乏特征。一种这样的miRNA,miRNA-21(miR-21), 在系统性红斑狼疮(SLE)患者中上调,并在小鼠模型中促进各种疾病。 这些包括实验性自身免疫性脑脊髓炎(EAE),哮喘,癌症,以及我们对它的作用的研究结果 Toll样受体7(TLR 7)驱动的SLE小鼠。我们发现TLR 7过表达SLE易感B6.Sle1bYaa miR-21缺陷小鼠(Sle 1bYaamiR-21-/-)的生殖中心(GC)B细胞、滤泡辅助T细胞(Tfh) 细胞和浆细胞(PC)反应。Sle 1bYaamiR-21-/-小鼠的这些反应与以下因素密切相关: 自身抗体减少,脾和骨髓产生自身抗体的抗体形成细胞(AFC) 应答这些数据证实了miR-21在B细胞耐受性和自身免疫性丧失中的作用, 需要确定miR-21促进自身抗体的机制(资助的重点) 生产和SLE。这将填补知识空白,并可能有助于发现迫切需要的有针对性的 SLE是一种使人衰弱的疾病,影响数百万美国人和世界各地的人们。TLR信号, 特别是TLR 7,在人和鼠模型中促进SLE,并且是有吸引力的治疗靶点。TLR7 信号传导激活NF-κ B炎症信号传导途径。TLR 7上调B细胞中miR-21的表达 它可以靶向NF-kB信号传导的负调节因子Peli 1,尽管miR-21在调节NF-κ B信号传导中的作用是不确定的。 目前尚不清楚通过靶向Peli 1在狼疮易感性B细胞中进行的kB信号传导。初步数据显示,B 与对照Sle 1bYaa B细胞相比,Sle 1bYaamiR-21-/-小鼠具有增加的Peli 1表达。此外,本发明还提供了一种方法, 先前的研究表明TLR信号传导参与代谢重编程,主要是通过激活 PI 3 K/Akt/mTOR通路在各种免疫条件下的作用,尽管该通路在TLR 7介导的免疫应答中的作用已经被证实。 SLE中B细胞的代谢重编程尚不清楚。miR-21还显示调节PI 3 K/Akt/mTOR 然而,其在调节TLR 7驱动的SLE中的B细胞代谢中的作用尚不清楚。 有趣的是,我们对来自TLR 7诱导模型的B细胞的RNA-seq分析显示负富集基因 在不存在miR-21的情况下,PI 3 K/Akt/mTOR通路中。初步数据显示, 过表达的Sle 1bYaa B细胞中的细胞外酸化(ECAR)和耗氧(OCR)速率 TLR 7与Sle 1 B B细胞相比,表明响应TLR 7信号传导的更有活力的表型。 相反,与Sle 1bYaa B细胞相比,Sle 1bYaamiR-21-/- B细胞表现出降低的ECAR和OCR。我们 假设miR-21通过以下方式促进TLR 7驱动的系统性自身免疫应答和SLE疾病: 调节B细胞中的TLR 7-NF-kB信号传导和代谢重编程。提出的假设和具体 目的将有助于阐明miR-21驱动自身免疫反应和狼疮性肾炎的机制, 并将告知我们miR-21或miR-21调节的通路是否可以成为SLE的治疗靶点。

项目成果

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Ziaur Rahman其他文献

Ziaur Rahman的其他文献

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{{ truncateString('Ziaur Rahman', 18)}}的其他基金

IRF7-mediated development of autoreactive B cells and SLE
IRF7 介导的自身反应性 B 细胞和 SLE 的发育
  • 批准号:
    10888832
  • 财政年份:
    2021
  • 资助金额:
    $ 54.37万
  • 项目类别:
IRF7-mediated development of autoreactive B cells and SLE
IRF7 介导的自身反应性 B 细胞和 SLE 的发育
  • 批准号:
    10277067
  • 财政年份:
    2021
  • 资助金额:
    $ 54.37万
  • 项目类别:
IRF7-mediated development of autoreactive B cells and SLE
IRF7 介导的自身反应性 B 细胞和 SLE 的发育
  • 批准号:
    10437008
  • 财政年份:
    2021
  • 资助金额:
    $ 54.37万
  • 项目类别:
"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"
“狼疮易感位点对外周 B 细胞耐受性的干扰”
  • 批准号:
    8507140
  • 财政年份:
    2011
  • 资助金额:
    $ 54.37万
  • 项目类别:
"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"
“狼疮易感位点对外周 B 细胞耐受性的干扰”
  • 批准号:
    8704864
  • 财政年份:
    2011
  • 资助金额:
    $ 54.37万
  • 项目类别:
"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"
“狼疮易感位点对外周 B 细胞耐受性的干扰”
  • 批准号:
    8564791
  • 财政年份:
    2011
  • 资助金额:
    $ 54.37万
  • 项目类别:
"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"
“狼疮易感位点对外周 B 细胞耐受性的干扰”
  • 批准号:
    8183980
  • 财政年份:
    2011
  • 资助金额:
    $ 54.37万
  • 项目类别:
"Perturbation of peripheral B cell tolerance by the lupus susceptibility loci"
“狼疮易感位点对外周 B 细胞耐受性的干扰”
  • 批准号:
    8318614
  • 财政年份:
    2011
  • 资助金额:
    $ 54.37万
  • 项目类别:
Impact of lupus susceptibility loci on peripheral tolerance and onset of disease
狼疮易感位点对外周耐受性和疾病发作的影响
  • 批准号:
    7846768
  • 财政年份:
    2008
  • 资助金额:
    $ 54.37万
  • 项目类别:
Impact of lupus susceptibility loci on peripheral tolerance and onset of disease
狼疮易感位点对外周耐受性和疾病发作的影响
  • 批准号:
    7669145
  • 财政年份:
    2008
  • 资助金额:
    $ 54.37万
  • 项目类别:

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