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
- 来源:
- 关键词:AcuteAcute T Cell LeukemiaAdultAgingAnimal ModelAntigensBacteriaCD4 Positive T LymphocytesCD40 LigandCD8-Positive T-LymphocytesCD8B1 geneCell LineageCellsCellular ImmunityDiagnosisEnsureEnterobacteria phage P1 Cre recombinaseEpigenetic ProcessEtiologyFOXP3 geneGene TargetingGenesHematopoietic stem cellsImmuneImmune System DiseasesImmune responseImmunologic Deficiency SyndromesInfection ControlInheritedKnowledgeLymphoblastic LeukemiaLymphocyteMalignant - descriptorMalignant NeoplasmsMature T-LymphocyteMethyltransferaseModelingMouse StrainsOutcomePathway interactionsPhysiologicalProcessProductionProtein IsoformsPublic HealthPublished CommentRecruitment ActivityRegulationRoleSpecific qualifier valueSpecificityT-Cell DevelopmentT-LymphocyteTestingThymus GlandTumor SuppressionTumor Suppressor ProteinsVirusbasebeta catenincancer therapychemotherapycytotoxicgenetic analysishistone modificationimprovedinduced pluripotent stem cellleukemia/lymphomamutantnew therapeutic targetnotch proteinnovel strategiespathogenprogenitorpublic health relevancereconstitutionsealthymocytetooltranscription factortranscriptometranslational medicine
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(由申请人提供):免疫缺陷(遗传性或获得性)和淋巴细胞恶性肿瘤是两种主要的免疫疾病,对公众健康构成严重威胁。首先,成人T细胞的损失(例如由于化疗或衰老)严重损害细胞免疫。不同的CD 4+和CD 8 + T细胞身份是如何建立和维持的,目前仍然是一个悬而未决的问题。其次,急性T细胞淋巴母细胞性白血病/淋巴瘤(T-ALL)是由胸腺中发育中的T细胞转化诱导的。需要阐明有助于T-ALL启动和增殖的因素/途径,以改善诊断和开发新的靶向治疗。 Tcf 1和Lef 1转录因子在T细胞发育中具有重要作用。我们还表明,Tcf 1的功能作为一个肿瘤抑制剂,通过抑制Lef 1和Notch在早期胸腺细胞的表达。Tcf 1和Lef 1与Wnt-β-连环蛋白途径最显著相关;然而,关于β-连环蛋白在T细胞发育和恶性肿瘤中的生理作用的长期争议仍未解决. 通过将Tcf 1和Lef 1条件性靶向于CD 4 + CD 8+双阳性(DP)胸腺细胞,我们发现Tcf 1/Lef 1双缺陷的CD 8 + T细胞显示出不适当的CD 4+谱系基因表达,包括CD 4辅助受体本身、CD 40配体、Rogt和Foxp 3,而无需预先活化。我们假设Tcf 1和Lef 1通过表观遗传学沉默CD 4+相关基因来封闭CD 8 + T细胞的身份。我们已经产生了一个真正的β-连环蛋白无效突变体和另一个小鼠品系,其中Tcf 1长同种型被消融,因此Tcf 1-β-连环蛋白相互作用被消除。有了这些新的工具,我们将测试Tcf 1和Lef 1使用β-连环蛋白依赖和β-连环蛋白独立的机制来调节胸腺细胞的成熟和转化的假设。我们的具体目标是:具体目标1。探讨Tcf 1和Lef 1调节CD 8 + T细胞特性的机制。具体目标2。阐明β-catenin及其与Tcf 1/Lef 1相互作用在T细胞发育和恶性肿瘤中的作用。 这些研究将确定第一个转录因子及其与表观遗传机制的相互作用,表观遗传机制负责调节CD 8 + T细胞的身份。新的动物模型将确保前所未有的清晰度,以解决长期存在的争议β-连环蛋白。这些结果将为免疫细胞的身份和Wnt-β-catenin通路的参与建立新的范式。这些信息将确定将造血祖细胞或iPS细胞定向为具有所需抗原特异性的成熟T细胞的关键调控点,从而有助于改善免疫重建和靶向的基于细胞的癌症治疗。
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)
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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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