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
- 来源:
- 关键词:AffectAmericanAntibodiesAsthmaAttenuatedAutoantibodiesAutoimmuneAutoimmune ResponsesAutoimmunityAutomobile DrivingB-Cell ActivationB-LymphocytesBinding SitesBone MarrowCellsCellular Metabolic ProcessCre lox recombination systemDataDevelopmentDiseaseDisease ProgressionExhibitsExperimental Autoimmune EncephalomyelitisFRAP1 geneGene ExpressionGenesGrantHelper-Inducer T-LymphocyteHumanImmuneImmunityInflammatoryInterferon Type IKnowledgeLearningLigandsLupus NephritisMalignant NeoplasmsMediatingMetabolicMetabolic PathwayMetabolismMicroRNAsModelingMusNF-kappa BOligonucleotidesOnset of illnessOxygen ConsumptionPIK3CG genePathway interactionsPatientsPersonsPhenotypePlasma CellsProductionPromoter RegionsRegulationRegulator GenesRoleSignal PathwaySignal TransductionStructure of germinal center of lymph nodeSystemic Lupus ErythematosusTLR7 geneTamoxifenTestingautoreactive B cellcomparison controlextracellularhuman modelinducible Cremouse modelmutantoverexpressionposttranscriptionalresponsesystemic autoimmunitytargeted treatmenttherapeutic targettranscription factortranscriptome sequencing
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
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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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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