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

基本信息

  • 批准号:
    8658530
  • 负责人:
  • 金额:
    $ 28.64万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-06-14 至 2014-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Epigenetic downregulation of the antibody response and inhibition of autoimmunity Epigenetic marks (including histone modifications, DNA methylation and microRNAs) "interact" with genetic programs to regulate B cell functions, such as class switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation, thereby informing the antibody response. Epigenetic dysregulation can result in aberrant antibody responses, and compound genetic susceptibility to mediate autoimmunity, including systemic lupus (SLE), in which heavily mutated and class-switched (mainly IgG) autoantibodies to nuclear antigens, as secreted by large numbers of plasma cells, produce widespread tissue and organ injury. Prompted by our compelling preliminary findings in human and mouse B cells in vitro, and in normal and lupus-prone mice, we hypothesize that the epigenetic modulators histone deacetylase inhibitors (HDIs) inhibit CSR/SHM, plasma cell differentiation and, therefore, specific antibody and autoantibody responses, and prevent autoimmunity and "cure" mice in an advanced stage of lupus. We also argue that HDIs inhibit antibody and autoantibody responses by upregulating expression of selected microRNAs through enhanced acetylation and transcription of those microRNA host genes. As suggested by our preliminary data, we contend that HDIs upregulate miR-155, miR-181b, miR-93 to downregulate AID (central to CSR/SHM), miR- 146a to downregulate transcription factors Irf5 and (through Stat1) T-bet (important in CSR to IgG2a and lupus), miR-127 and miR-125b to downregulate Blimp1/Xbp1 (critical for plasma cell differentiation). The Casali lab is uniquely poised to test these novel hypotheses, owing to its record of accomplishment in B cell biology, molecular CSR/SHM and autoimmunity over the last 25 years, and the recently established cutting-edge epigenetic approaches. We will analyze the impact of HDIs (valproic acid, butyrate, suberoylanilide hydroxamic acid) on T-dependent and T-independent antibody responses in normal C57BL/6 and Balb/c mice, and autoantibody responses and autoimmunity in lupus-prone MRL/Faslpr/lpr and B6.NZM/Sle1.Sle2.Sle3 mice (Aim 1). We will address the downregulation of AID, Irf5, T-bet, Blimp1 and Xbp1, as targeted by (HDI-mediated) upregulation of miR-155, miR-181b, miR-93, miR-146a, miR-127 and miR-125b through enhanced acetylation of these microRNA "host genes" (Aim 2). Finally, we will define the role of microRNAs in mediating HDI inhibition of autoimmunity using lupus-prone mice lacking Dicer or Drosha in AID+ B cells or lacking microRNA targeting sites in Aicda and Prdm1 mRNAs, and identify genome-wide HDI-susceptible microRNA/target mRNA pairs in lupus mice (Aim 3). Our proposal is highly significant and innovative, as it addresses core epigenetic mechanisms of lupus and will have sustained impact on the fields of epigenetics, immunoregulation and autoimmunity. Finally, it is exquisitely translational, as (at the time when expensive biologics enter clinical trials) it provies a sound mechanistic basis for use of inexpensive and available epigenetic modulators as therapeutics in autoimmune diseases. !
描述(由申请人提供):抗体反应的表观遗传下调和自身免疫抑制表观遗传标记(包括组蛋白修饰、DNA 甲基化和 microRNA)与调节 B 细胞功能的遗传程序“相互作用”,例如类别转换 DNA 重组 (CSR)、体细胞超突变 (SHM) 和浆细胞分化,从而通知抗体反应。表观遗传失调可导致抗体反应异常,以及介导自身免疫的复合遗传易感性,包括系统性狼疮 (SLE),其中由大量浆细胞分泌的针对核抗原的严重突变和类别转换(主要是 IgG)自身抗体,会产生广泛的组织和器官损伤。 受我们在体外人类和小鼠 B 细胞以及正常和狼疮易感小鼠中的令人信服的初步发现的启发,我们假设表观遗传调节剂组蛋白脱乙酰酶抑制剂 (HDI) 抑制 CSR/SHM、浆细胞分化,从而抑制特异性抗体和自身抗体反应,并预防自身免疫并“治愈”晚期阶段的小鼠。 狼疮。我们还认为,HDI 通过增强这些 microRNA 宿主基因的乙酰化和转录来上调所选 microRNA 的表达,从而抑制抗体和自身抗体反应。正如我们的初步数据所示,我们认为 HDIs 上调 miR-155、miR-181b、miR-93 来下调 AID(CSR/SHM 的核心),miR-146a 下调转录因子 Irf5 和(通过 Stat1)T-bet(在 IgG2a 和狼疮的 CSR 中很重要),miR-127 和 miR-125b 下调Blimp1/Xbp1(关键 用于浆细胞分化)。 Casali 实验室凭借过去 25 年在 B 细胞生物学、分子 CSR/SHM 和自身免疫方面的成就记录,以及最近建立的尖端表观遗传学方法,为测试这些新假设做好了独特的准备。我们将分析 HDIs(丙戊酸、丁酸、辛二酰苯胺异羟肟酸)对正常 C57BL/6 和 Balb/c 小鼠中 T 依赖性和 T 非依赖性抗体反应的影响,以及狼疮倾向 MRL/Faslpr/lpr 和 B6.NZM/Sle1.Sle2.Sle3 小鼠中自身抗体反应和自身免疫的影响 (目标 1)。我们将解决 AID、Irf5、T-bet、Blimp1 和 Xbp1 的下调,通过增强这些 microRNA“宿主基因”的乙酰化,以(HDI 介导的)miR-155、miR-181b、miR-93、miR-146a、miR-127 和 miR-125b 上调为目标(目标 2)。最后,我们将使用 AID+ B 细胞中缺乏 Dicer 或 Drosha 或 Aicda 和 Prdm1 mRNA 中缺乏 microRNA 靶向位点的狼疮易感小鼠来定义 microRNA 在介导 HDI 抑制自身免疫中的作用,并鉴定狼疮小鼠中全基因组 HDI 易感的 microRNA/靶 mRNA 对(目标 3)。我们的建议非常重要和创新,因为它解决了狼疮的核心表观遗传机制,并将对表观遗传学、免疫调节和自身免疫领域产生持续影响。最后,它具有出色的转化性,因为(当昂贵的生物制剂进入临床试验时)它为使用廉价且可用的表观遗传调节剂作为自身免疫性疾病的治疗方法提供了良好的机制基础。 !

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:
    $ 28.64万
  • 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:
    10392220
  • 财政年份:
    2021
  • 资助金额:
    $ 28.64万
  • 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:
    $ 28.64万
  • 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:
    $ 28.64万
  • 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:
    $ 28.64万
  • 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:
    $ 28.64万
  • 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:
    $ 28.64万
  • 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:
    $ 28.64万
  • 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:
    $ 28.64万
  • 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:
    $ 28.64万
  • 项目类别:

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