Epigenetics of the autoantibody response in systemic lupus

系统性狼疮自身抗体反应的表观遗传学

基本信息

  • 批准号:
    10392220
  • 负责人:
  • 金额:
    $ 73.33万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-24 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT. Epigenetics of the autoantibody response in systemic lupus. Like “mature” antibody responses to viruses and bacteria, the lupus autoantibody response requires B cell class- switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation. As we have shown, epigenetic factors, including histone modifiers (such as Sirt1) and inhibitors (such as butyrate) modulate B cell expression of AID (gene: AICDA/Aicda) and Blimp-1 (PRDM1/Prdm1), which are critically for CSR/SHM and plasma cell differentiation, respectively. Towards a better definition of the epigenetic landscape of lupus B cells, we hypothesize that Tet2, a key epigenetic factor, mediates the lupus autoantibody response, as prompted the B cell-intrinsic role of Tet2 in CSR/SHM and plasma cell differentiation (our recent findings). We argue that Tet2 is induced by the stimuli that induce B cell CSR/SHM and plasma cell differentiation, and it is upregulated in lupus B cells. We also argue that Tet2 boosts transcription of Aicda and Prdm1 through its Fe2+ and a- ketoglutarate (a-KG)-dependent catalytic activity for DNA demethylation as well as its non-catalytic function, i.e., recruiting Ogt (encoded by X-linked OGT/Ogt) to these loci to effect histone glycosylation. Finally, we contend that B cell Tet2 transduces hormonal, nutritional and metabolic cues into epigenetic changes to modulate autoantibody responses, as Tet2 transcription could be upregulated by estrogen (E2, our preliminary data) and vitamin A, and Tet2 is activated by vitamin C, but inhibited by fumarate (a metabolite and a-KG competitor) – as shown by us, E2 boosts AID expression, which would enhance females’ antibody and autoantibody responses. With extensive experience in and commitment to the mechanistic understanding of human and mouse lupus autoantibody responses, we are uniquely poised to test our hypotheses using molecular B cell biology systems, cutting-edge epigenetic tools (hydroxylmethyl DNA analysis, bisulfite and oxidative bisulfite conversion, ChIP and ATAC-Seq), genetically modified mice (TgAicda-creTet2fl/fl, Tet2HxD-mut/HxD-mut and Tet2Ogt-mut/Ogt-mut knockin mice, TgAicda-creOgtfl/fl, Tet2HxD-mut/HxD-mutTgAicda-creOgtfl/fl, MRL/Lpr TgAicda-creTet2fl/fl, MRL/Lpr Tet2HxD-mut/HxD-mut and MRL/Lpr TgAicda-creOgtfl/fl), proprietary humanized H-Mice® and Lupus-H-Mice® models. Aim 1 addresses human and mouse B cell differentiation stage-specific (resting, activated, plasma and memory cell) regulation of Tet2, Tet2 protein stability, E2 upregulation of Tet2 transcripts and underlying mechanisms. Aim 2 addresses the B cell- intrinsic role of Tet2 in promoting AID and Blimp-1 expression, the underlying mechanisms (active DNA demethylation and Ogt-mediated histone glycosylation), and potentiation effect of Tet2 inducer vitamin A and activator vitamin C, and suppressive effect of Tet2 catalytic inhibitor (fumarate, TET-IN-C35 or Bobcat339) alone or combined with Ogt ablation or Tet2Ogt-mut/Ogt-mut knockin. Aim 3 analyzes dysregulation of Tet2 and Tet2- mediated epigenetic mechanisms in human and mouse lupus B cells, addresses the role of Tet2 in lupus, and explores Tet2 inhibitors and Ogt inhibitor ST045849 as lupus therapeutics. Our experiments will unveil novel and targetable epigenetic mechanisms that integrate environmental cues to inform the lupus autoantibody response.
项目总结/抽象。系统性狼疮自身抗体反应的表观遗传学。

项目成果

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Paolo Casali其他文献

Paolo Casali的其他文献

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{{ truncateString('Paolo Casali', 18)}}的其他基金

Epigenetics of the autoantibody response in systemic lupus
系统性狼疮自身抗体反应的表观遗传学
  • 批准号:
    10494251
  • 财政年份:
    2021
  • 资助金额:
    $ 73.33万
  • 项目类别:
Epigenetics of the autoantibody response in systemic lupus
系统性狼疮自身抗体反应的表观遗传学
  • 批准号:
    10681392
  • 财政年份:
    2021
  • 资助金额:
    $ 73.33万
  • 项目类别:
Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
  • 批准号:
    9198631
  • 财政年份:
    2014
  • 资助金额:
    $ 73.33万
  • 项目类别:
Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
  • 批准号:
    8996116
  • 财政年份:
    2014
  • 资助金额:
    $ 73.33万
  • 项目类别:
Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
  • 批准号:
    9205214
  • 财政年份:
    2014
  • 资助金额:
    $ 73.33万
  • 项目类别:
Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
  • 批准号:
    8639370
  • 财政年份:
    2014
  • 资助金额:
    $ 73.33万
  • 项目类别:
Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
  • 批准号:
    8794403
  • 财政年份:
    2014
  • 资助金额:
    $ 73.33万
  • 项目类别:
Intrinsic B cell epigenetic regulation of antibody and autoantibody responses by Sirt1
Sirt1 对抗体和自身抗体反应的内在 B 细胞表观遗传调控
  • 批准号:
    10335163
  • 财政年份:
    2013
  • 资助金额:
    $ 73.33万
  • 项目类别:
Intrinsic B cell epigenetic regulation of antibody and autoantibody responses by Sirt1
Sirt1 对抗体和自身抗体反应的内在 B 细胞表观遗传调控
  • 批准号:
    10544531
  • 财政年份:
    2013
  • 资助金额:
    $ 73.33万
  • 项目类别:
Epigenetic downregulation of the antibody response and inhibition of autoimmunity
抗体反应的表观遗传下调和自身免疫的抑制
  • 批准号:
    8658530
  • 财政年份:
    2013
  • 资助金额:
    $ 73.33万
  • 项目类别:

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