bZIP proteins, NFAT, and lymphocyte gene induction

bZIP 蛋白、NFAT 和淋巴细胞基因诱导

基本信息

  • 批准号:
    8761495
  • 负责人:
  • 金额:
    $ 67.89万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-01 至 2019-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The calcium/ calcineurin/ NFAT pathway is essential for the adaptive immune response, a point underscored by the clinical efficacy of the calcineurin inhibitors cyclosporin A (CsA) and FK506. NFAT also plays an important role in the development and function of many other organs and cell types - neurons, heart, skeletal and smooth muscle, bone, skin, pancreas, and the vasculature. Surprisingly, however, there has not yet been a detailed examination, at a genome-wide level, of how NFAT transcription factors bind cis-regulatory DNA elements and change the transcriptional profiles of cells. In this application, we address this point for CD4+ Th1 and CD8+ cytolytic T cells (CTL). A striking feature of NFAT proteins is their ability to form tight complexes with unrelated transcription factors such as AP-1 (Fos-Jun) on "composite" elements in DNA. We have shown that NFAT in the absence of its partner AP-1 induces a negative regulatory programme of gene expression (T cell 'anergy' or 'exhaustion') that is distinct from the programme of T cell activation induced by NFAT: AP-1 complexes. Indeed, our preliminary data suggest that in the absence of AP-1, NFAT potentially functions as a 'master regulator' of CD8+ T cell exhaustion, a hypothesis that will be tested here. In Aim 1 of the application, we will examine the binding of the three immune-related NFAT proteins - NFAT1, NFAT2 and NFAT4 - to regulatory regions in genomic DNA of Th1 cells and CTL, under conditions of cooperation or lack of cooperation with AP-1. We will perform chromatin immunoprecipitation (ChIP) followed by next-generation sequencing (ChIP-seq), and a variant procedure known as ChIP-exo that more closely defines the binding sites for these transcription factors in DNA. We will also define the gene expression patterns regulated by these wild type and mutant NFAT proteins, by performing RNA-sequencing (RNA-seq) for steady-state or 'nascent' (chromatin-associated) RNA-sequencing on cells expressing the proteins. In Aim 2, we will repeat these experiments in human T cells. In Aim 3, we will implement a novel high-throughput screen to identify compounds that block the NFAT: AP-1 interaction without affecting the binding of NFAT to DNA or the formation of NFAT complexes with other partners such as FOXP3. In Aim 4, we will relate the patterns of gene expression defined in vitro in Aims 1 and 2 to the patterns obtained during immune responses in vivo, and ask whether T cells expressing mutant NFAT proteins that cannot cooperate with AP-1 induce a more profound phenotype of T cell anergy/ exhaustion during viral infections. From a clinical perspective, our project is very relevant to cancer immunotherapy and the treatment of viral infections, since CD8+ T cell exhaustion limits T cell responses in tumour-infiltrating CTL and during chronic viral infections.
描述(由申请人提供):钙/钙调磷酸酶/ NFAT通路对适应性免疫应答至关重要,钙调磷酸酶抑制剂环孢素a (cyclosporin a, CsA)和FK506的临床疗效强调了这一点。NFAT在许多其他器官和细胞类型的发育和功能中也起着重要作用——神经元、心脏、骨骼和平滑肌、骨骼、皮肤、胰腺和脉管系统。然而,令人惊讶的是,目前还没有在全基因组水平上详细检查NFAT转录因子如何结合顺式调控DNA元件并改变细胞的转录谱。在本应用程序中,我们针对CD4+ Th1和CD8+细胞溶解T细胞(CTL)解决这一点。NFAT蛋白的一个显著特征是它们能够与不相关的转录因子(如AP-1)形成紧密复合物

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Patrick Hogan其他文献

Patrick Hogan的其他文献

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{{ truncateString('Patrick Hogan', 18)}}的其他基金

NFAT, bZIP proteins, and transcriptional programs in lymphocytes
NFAT、bZIP 蛋白和淋巴细胞中的转录程序
  • 批准号:
    9974252
  • 财政年份:
    2014
  • 资助金额:
    $ 67.89万
  • 项目类别:
Nanoscale regulation of store-operated calcium entry through STIM-ORAI signalling
通过 STIM-ORAI 信号传导纳米级调节钙库操作的钙进入
  • 批准号:
    8675111
  • 财政年份:
    2014
  • 资助金额:
    $ 67.89万
  • 项目类别:
NFAT, bZIP proteins, and transcriptional programs in lymphocytes
NFAT、bZIP 蛋白和淋巴细胞中的转录程序
  • 批准号:
    10350619
  • 财政年份:
    2014
  • 资助金额:
    $ 67.89万
  • 项目类别:
bZIP proteins, NFAT, and lymphocyte gene induction
bZIP 蛋白、NFAT 和淋巴细胞基因诱导
  • 批准号:
    8899429
  • 财政年份:
    2014
  • 资助金额:
    $ 67.89万
  • 项目类别:
NFAT, bZIP proteins, and transcriptional programs in lymphocytes
NFAT、bZIP 蛋白和淋巴细胞中的转录程序
  • 批准号:
    10580710
  • 财政年份:
    2014
  • 资助金额:
    $ 67.89万
  • 项目类别:
Nanoscale regulation of store-operated calcium entry through STIM-ORAI signalling
通过 STIM-ORAI 信号传导纳米级调节钙库操作的钙进入
  • 批准号:
    8840980
  • 财政年份:
    2014
  • 资助金额:
    $ 67.89万
  • 项目类别:
Bioinformatic strategy to identify calcineurin interactors in the human proteome
识别人类蛋白质组中钙调磷酸酶相互作用因子的生物信息策略
  • 批准号:
    8444062
  • 财政年份:
    2010
  • 资助金额:
    $ 67.89万
  • 项目类别:
STIM-ORAI signaling and other calcium influx pathways in lymphocytes
淋巴细胞中的 STIM-ORAI 信号传导和其他钙流入途径
  • 批准号:
    8889028
  • 财政年份:
    2005
  • 资助金额:
    $ 67.89万
  • 项目类别:
Signal transduction and gene induction in lymphocytes
淋巴细胞中的信号转导和基因诱导
  • 批准号:
    8713901
  • 财政年份:
    1991
  • 资助金额:
    $ 67.89万
  • 项目类别:
Signal transduction and gene induction in lymphocytes
淋巴细胞中的信号转导和基因诱导
  • 批准号:
    10459427
  • 财政年份:
    1991
  • 资助金额:
    $ 67.89万
  • 项目类别:

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