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.
项目概要
MicroRNA (miRNA) 是免疫和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 miRNA 的特征仍不清楚。其中一种 miRNA,miRNA-21 (miR-21),是
在系统性红斑狼疮 (SLE) 患者中表达上调,并在小鼠模型中促进多种疾病。
其中包括实验性自身免疫性脑脊髓炎 (EAE)、哮喘、癌症以及我们对其作用的发现
小鼠中 Toll 样受体 7 (TLR7) 驱动的 SLE。我们发现 TLR7 过度表达易患 SLE 的 B6.Sle1bYaa
miR-21 缺陷的小鼠 (Sle1bYaamiR-21-/-) 生发中心 (GC) B 细胞和滤泡辅助 T (Tfh) 减少
细胞和浆细胞(PC)反应。 Sle1bYaamiR-21-/- 小鼠的这些反应与
自身抗体减少,以及脾和骨髓产生自身抗体的抗体形成细胞(AFC)
回应。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,这
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目标
SLE 是一种使人衰弱的疾病,影响着数百万美国人和世界各地的人们。 TLR信号传导,
尤其是 TLR7,在人类和小鼠模型中促进 SLE,并且是一个有吸引力的治疗靶点。 TLR7
信号传导激活 NF-kB 炎症信号通路。 TLR7 上调 B 细胞中 miR-21 的表达
它可以靶向 NF-kB 信号转导的负调节因子 Peli1,尽管 miR-21 在调节 NF-
尚不清楚易患 SLE 的 B 细胞中通过靶向 Peli1 的 kB 信号传导。初步数据显示,B 细胞来自
与对照 Sle1bYaa B 细胞相比,Sle1bYaamiR-21-/- 小鼠 Peli1 表达增加。此外,
之前的研究表明 TLR 信号传导参与代谢重编程,主要是通过激活
PI3K/Akt/mTOR 通路在各种免疫条件下的作用,尽管该通路在 TLR7 介导中的作用
SLE 中 B 细胞的代谢重编程尚不清楚。 miR-21 还被证明可以调节 PI3K/Akt/mTOR
各种模型中的路径;然而,其在 TLR7 驱动的 SLE 中调节 B 细胞代谢的作用尚不清楚。
有趣的是,我们对 TLR7 诱导模型中的 B 细胞进行 RNA-seq 分析,结果显示基因负富集
在 miR-21 缺失的情况下,PI3K/Akt/mTOR 通路中的额外的初步数据显示增加
Sle1bYaa B 细胞过表达的细胞外酸化 (ECAR) 和耗氧 (OCR) 率
TLR7 与 Sle1b B 细胞相比,表明响应 TLR7 信号传导的能量更高的表型。
相反,与 Sle1bYaa B 细胞相比,Sle1bYaamiR-21-/- B 细胞表现出 ECAR 和 OCR 降低。我们
假设 miR-21 通过 TLR7 驱动的系统性自身免疫反应和 SLE 疾病促进
调节 B 细胞中的 TLR7-NF-kB 信号传导和代谢重编程。提出的假设和具体
目标将有助于阐明 miR-21 驱动自身免疫反应和狼疮肾炎的机制
并将告诉我们 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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