Genome-wide networks that modulate the T-lineage cell fate
调节 T 谱系细胞命运的全基因组网络
基本信息
- 批准号:8608279
- 负责人:
- 金额:$ 38.22万
- 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:2014-05-15 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAntigen ReceptorsAttenuatedB-Cell DevelopmentBinding SitesCell LineageCellsChromosomesComplexDNA BindingDNA Sequence RearrangementDevelopmentE proteinEnhancersEpithelialExclusionGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGenomeGenomicsGlobal ChangeGoalsHelix-Turn-Helix MotifsImmune System DiseasesInstructionLinkLocationMalignant NeoplasmsMediatingMolecularNamesNuclearPathway interactionsPlayPopulationProcessProtein FamilyProteinsRoleSeriesSignal TransductionStructureSwitch GenesT-Cell DevelopmentT-LymphocyteTCF3 genebasegenome wide association studygenome-widehelix-loop-helix protein differentiation inhibitormembernotch proteinnovelpreferenceprogenitorprogramspromoterresponsethymocytetranscription factor
项目摘要
The long-range goals of our studies are to understand the mechanisms that enforce the γδT and pre-TCR
checkpoints. We would like to describe these checkpoints in terms of global networks involving
transcriptional regulators, signaling components and survival factors. Previously, we as well as others
have demonstrated that E- and Id-proteins play critical roles in enforcing the γδ, pre-TCR and TCR
checkpoints. Most prominent among the E-proteins are the E2A gene products, E12 and E47. Two
additional members that are closely related to E2A, named E2-2 and HEB, also belong to the E-protein
family. The DNA binding activities of E-proteins are attenuated by a subset of helix-loop-helix (HLH)
proteins, named ld1-4.
E-proteins levels are high in T cell progenitors where they initiate TCRy, δ as well β locus rearrangement,
activate the expression of genes encoding for proteins involved in Notch- and pre-TCR signaling arid
antagonize proliferation. Once a γδ or pre-TCR complex is assembled, IdS levels are elevated to suppress
E2A DNA binding.
Here we propose to continue these studies. We would use functional studies, genome-wide analyses and
computational approaches to determine the mechanisms that underpin γδ versus β selection. We would
identify factors that cooperate with E-proteins to enforce the pre-TCR checkpoints. We would examine
whether gradients of E-protein activity modulate DNA binding site preferences as well as enhancer
repertoire selection beyond the pre-TCR checkpoint. We would examine how Notch- and pre-TCR
signaling act in concert to modulate binding site as well as enhancer selection. We would describe γδ T
cell development in terms of global networks of enhancer repertoires, interacting transcription factors,
signaling components and survival factors. We would examine how differences in signaling by the pre-
TCR and γδ TCR affect E2A occupancy and binding site selection. Finally, we would examine how these
networks change during developmental progression and how such changes relate to enforcement of the γδ
and pre-TCR checkpoints.
RELEVANCE (See instructions):
It has been established that an important population of cells, named γδ T cells, play critical roles in
preserving epithelial structures that function as barriers. The proposal described here is aimed to
understand the molecular mechanisms that promote their developmental progression. These studies may
permit novel avenues for the treatment of immune diseases and interference with the development of
malignancies.
我们研究的长期目标是了解执行γδT和前TCR的机制
检查站。我们想从全球网络的角度来描述这些检查站,这些网络包括
转录调节因子、信号成分和生存因子。以前,我们和其他人一样
已经证明E-和ID-蛋白在执行γδ、前TCR和TCR中起关键作用
检查站。在E蛋白中最突出的是E2a基因产物E12和E47。二
与E2a密切相关的其他成员,称为E2-2和Heb,也属于E蛋白
一家人。E蛋白的DNA结合活性被螺旋-环-螺旋(HLH)的一个子集减弱
蛋白质,命名为ld1-4。
在启动TCRY、δ和β基因重排的T细胞前体中,E蛋白水平很高,
激活Notch和Pre-TCR信号转导相关蛋白编码基因的表达
抗增殖。一旦组装了γδ或前TcR复合体,ID水平就会升高,以抑制
E2ADNA结合。
在这里,我们建议继续进行这些研究。我们将使用功能研究、全基因组分析和
确定γδ与β选择的基础机制的计算方法。我们会
确定与E蛋白协同作用以加强TCR前检查点的因素。我们会检查
E蛋白活性梯度是否影响DNA结合位点偏好和增强子
超出TCR前检查点的曲目选择。我们将研究Notch-和Pre-TCR如何
信号协同作用调节结合位点和增强子的选择。我们会将γδT描述为
在全球增强子库网络、相互作用的转录因子、
信号成分和生存因素。我们将研究Pre-Pre信号的差异
TcR和γδTcR影响E2a的占位和结合位点的选择。最后,我们将研究这些
网络在发展过程中的变化以及这种变化与γδ的实施有何关系
以及TCR之前的检查站。
相关性(请参阅说明):
现已证实,一组重要的细胞,称为γδT细胞,在
保护起屏障作用的上皮结构。这里描述的建议旨在
了解促进其发育进程的分子机制。这些研究可能
允许治疗免疫性疾病和干扰发展的新途径
恶性肿瘤。
项目成果
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{{ truncateString('CORNELIS MURRE', 18)}}的其他基金
Molecular and physical mechanisms that underpin the αβ versus γδ T cell fate decision
支持 αβ 与 γδ T 细胞命运决定的分子和物理机制
- 批准号:
10462551 - 财政年份:2014
- 资助金额:
$ 38.22万 - 项目类别:
Molecular and physical mechanisms that underpin the αβ versus γδ T cell fate decision
支持 αβ 与 γδ T 细胞命运决定的分子和物理机制
- 批准号:
10226999 - 财政年份:2014
- 资助金额:
$ 38.22万 - 项目类别:
Molecular and physical mechanisms that underpin the αβ versus γδ T cell fate decision
支持 αβ 与 γδ T 细胞命运决定的分子和物理机制
- 批准号:
10685633 - 财政年份:2014
- 资助金额:
$ 38.22万 - 项目类别:
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