Tcf/Lef-b-catenin in T cell identity and cancer

Tcf/Lef-b-连环蛋白在 T 细胞身份和癌症中的作用

基本信息

  • 批准号:
    9208107
  • 负责人:
  • 金额:
    $ 38.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-03-15 至 2019-02-28
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Immunodeficiencies (inherited or acquired) and lymphocyte malignancy are two major immune disorders that pose grave threats to public health. Firstly, loss of T cells in adults (e.g. due to chemotherapy or ageing) severely compromises cellular immunity. How the distinct CD4+ and CD8+ T cell identities are established and maintained remains an unanswered puzzling question at present. Secondly, acute T cell lymphoblastic leukemia/lymphomas (T-ALLs) is induced by the transformation of developing T cells in the thymus. Elucidation of factors/pathways contributing to initiation and propagation of T-ALLs is required to improve diagnosis and develop novel targeted therapies. Tcf1 and Lef1 transcription factors are well documented to have essential roles in T cell development. We also showed that Tcf1 functions as a tumor suppressor by restraining Lef1 and Notch expression in early thymocytes. Tcf1 and Lef1 are most notably associated with the Wnt-ß-catenin pathway; however, the long- standing controversies regarding the physiological roles of ß-catenin in T cell development and malignancy remain unresolved. By conditionally targeting both Tcf1 and Lef1 at CD4+CD8+ double positive (DP) thymocytes, we found that Tcf1/Lef1 double deficient CD8+ T cells showed inappropriate expression of CD4+ lineage genes including the CD4 coreceptor itself, CD40 ligand, Rorgt and Foxp3 without prior activation. We hypothesize that Tcf1 and Lef1 seal off CD8+ T cell identity by epigenetically silencing CD4+-associated genes. We have generated a true ß-catenin null mutant and another mouse strain where Tcf1 long isoforms are ablated and hence Tcf1-ß- catenin interaction is abrogated. With these new tools, we will test the hypothesis that Tcf1 and Lef1 use both ß-catenin-dependent and -independent mechanisms to regulate thymocyte maturation and transformation. Our specific aims are: Specific Aim 1. To investigate the mechanisms by which Tcf1 and Lef1 regulate CD8+ T cell identity. Specific Aim 2. To elucidate the requirements of ß-catenin and its interaction with Tcf1/Lef1 in T cell development and malignancy. These studies will identify the first transcription factors and their interaction with epigenetic machinery that re responsible for regulation of CD8+ T cell identity. The new animal models will ensure unprecedented clarity to resolve the long-standing controversies over ß-catenin. The outcomes will establish new paradigms in immune cell identity and the involvement of Wnt-ß-catenin pathway. The information will identify critical regulatory points in directing hematopoietic progenitors or iPS cells to mature T cells with desired antigen specificity and thus help improve immune reconstitution and targeted, cell-based cancer therapy.
 描述(申请人提供):免疫缺陷(遗传性或获得性)和淋巴细胞恶性是两种严重威胁公共健康的主要免疫疾病。首先,成人T细胞的丧失(例如,由于化疗或衰老)严重损害细胞免疫。如何建立和维持不同的CD4+和CD8+T细胞特性目前仍是一个未解之谜。其次,急性T细胞淋巴母细胞性白血病/淋巴瘤(T-ALL)是由胸腺内发育中的T细胞转化引起的。为了改进诊断和开发新的靶向治疗方法,需要阐明T-ALL启动和传播的因素/途径。Tcf1和Lef1转录因子在T细胞发育中起着重要的作用。我们还表明,Tcf1通过抑制Lef1和Notch在早期胸腺细胞中的表达而发挥肿瘤抑制作用。Tcf1和Lef1与Wnt-?-catenin通路密切相关;然而,关于??-catenin在T细胞发育和恶性肿瘤中的生理作用的长期争论仍未解决。通过有条件地将Tcf1和Lef1同时靶向CD4+CD8+双阳性(DP)胸腺细胞,我们发现Tcf1/Lef1双缺陷CD8+T细胞在没有预先激活的情况下,表现出包括CD4辅受体本身、CD40配体、Rorgt和Foxp3在内的CD4+谱系基因的异常表达。我们假设Tcf1和Lef1通过表观遗传沉默CD4+相关基因来封闭CD8+T细胞的特性。我们已经产生了一个真正的ç-catenin缺失突变体和另一个小鼠品系,其中Tcf1长亚型被消融,因此Tcf1-ç-catenin相互作用被取消。通过这些新的工具,我们将检验Tcf1和Lef1使用?连环蛋白依赖和独立的机制来调节胸腺细胞成熟和转化的假设。我们的具体目的是:1.研究Tcf1和Lef1调节CD8+T细胞表型的机制。具体目的2.阐明B-连环蛋白及其与Tcf1/Lef1的相互作用在T细胞发育和恶性转化中的作用。这些研究将确定第一批转录因子及其与负责调节CD8+T细胞特性的表观遗传机制的相互作用。新的动物模型将确保前所未有的清晰度,以解决围绕ç-catenin的长期争议。这一结果将建立免疫细胞识别和参与Wnt-ü-catenin途径的新范式。这些信息将确定引导造血祖细胞或iPS细胞向具有所需抗原特异性的成熟T细胞转化的关键调节点,从而有助于改善免疫重建和靶向、基于细胞的癌症治疗。

项目成果

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会议论文数量(0)
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Hai-Hui Xue其他文献

Hai-Hui Xue的其他文献

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{{ truncateString('Hai-Hui Xue', 18)}}的其他基金

Modulating costimulation pathways to improve follicular helper T cell and antibody responses
调节共刺激途径以改善滤泡辅助 T 细胞和抗体反应
  • 批准号:
    10571687
  • 财政年份:
    2022
  • 资助金额:
    $ 38.13万
  • 项目类别:
Modulating costimulation pathways to improve follicular helper T cell and antibody responses
调节共刺激途径以改善滤泡辅助 T 细胞和抗体反应
  • 批准号:
    10367461
  • 财政年份:
    2022
  • 资助金额:
    $ 38.13万
  • 项目类别:
Targeting Tcf/Lef-transcriptional program in leukemic stem cells
靶向白血病干细胞中的 Tcf/Lef 转录程序
  • 批准号:
    10163369
  • 财政年份:
    2016
  • 资助金额:
    $ 38.13万
  • 项目类别:
Targeting Tcf/Lef-transcriptional program in leukemic stem cells
靶向白血病干细胞中的 Tcf/Lef 转录程序
  • 批准号:
    9212638
  • 财政年份:
    2016
  • 资助金额:
    $ 38.13万
  • 项目类别:
Targeting Tcf/Lef-transcriptional program in leukemic stem cells
靶向白血病干细胞中的 Tcf/Lef 转录程序
  • 批准号:
    9022091
  • 财政年份:
    2016
  • 资助金额:
    $ 38.13万
  • 项目类别:
Tcf1 programs CD8 T cell responses to enhance viral and cancer immunity
Tcf1 编程 CD8 T 细胞反应以增强病毒和癌症免疫力
  • 批准号:
    10396568
  • 财政年份:
    2015
  • 资助金额:
    $ 38.13万
  • 项目类别:
Tcf/Lef-b-catenin in T cell identity and cancer
Tcf/Lef-b-连环蛋白在 T 细胞身份和癌症中的作用
  • 批准号:
    8883981
  • 财政年份:
    2015
  • 资助金额:
    $ 38.13万
  • 项目类别:
Tcf1 programs CD8 T cell responses to enhance viral and cancer immunity
Tcf1 编程 CD8 T 细胞反应以增强病毒和癌症免疫力
  • 批准号:
    10611882
  • 财政年份:
    2015
  • 资助金额:
    $ 38.13万
  • 项目类别:
Decoding TCF1-controlled transcriptional program that promotes memory T cell fate
解码 TCF1 控制的转录程序,促进记忆 T 细胞的命运
  • 批准号:
    8487767
  • 财政年份:
    2013
  • 资助金额:
    $ 38.13万
  • 项目类别:
Decoding TCF1-controlled transcriptional program that promotes memory T cell fate
解码 TCF1 控制的转录程序,促进记忆 T 细胞的命运
  • 批准号:
    8650791
  • 财政年份:
    2013
  • 资助金额:
    $ 38.13万
  • 项目类别:

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    $ 38.13万
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