Epigenetic Regulation by WASP of Human TBX21 Gene Transcription Program
WASP 对人类 TBX21 基因转录程序的表观遗传调控
基本信息
- 批准号:8704452
- 负责人:
- 金额:$ 37.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-20 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:AsthmaAtopic DermatitisAutoimmune ProcessAutoimmune hemolytic anemiaAutoimmunityBindingBiochemicalCD4 Positive T LymphocytesCell Differentiation processCell NucleusCellsChIP-on-chipChildChromatinClinicalColitisComplexCytokine GeneDeoxyribonuclease IDevelopmentDiseaseDistalEnhancersEnzymesEpigenetic ProcessEventExhibitsFailureFunctional disorderGene ActivationGene TargetingGenesGenetic TranscriptionGenomeGenotypeHealthHelper-Inducer T-LymphocyteHistonesHumanHypersensitivityIL12RB1 geneIgEImmuneImmune responseImmunityImmunologic Deficiency SyndromesInfectionInterferon Type IIInterferonsKnowledgeLysineMalignant NeoplasmsMapsMediatingMessenger RNAMissense MutationModelingModificationMolecularMusMutateMutationNuclearNucleic Acid Regulatory SequencesOrgan TransplantationOutcomePathogenesisPathway interactionsPatientsPhenotypeProcessProteinsProteomePublicationsPublishingRNA InterferenceReadingRecruitment ActivityRegulationRegulator GenesRegulatory ElementRegulatory T-LymphocyteResearchRoleSTAT1 geneSTAT4 geneScienceSeriesSiteSpecific qualifier valueSystemic infectionT-LymphocyteTestingTh1 CellsTranscription InitiationTranscriptional ActivationTranscriptional RegulationWaspsWiskott-Aldrich SyndromeWitbasecytokinegenome-widehistone-binding proteinshuman diseaseimmune functionin vitro activityin vivoindexingmRNA Expressionnovelpathogenprogramspromoterprotein protein interactionresponsetherapeutic targettranscription factortranslational medicine
项目摘要
DESCRIPTION (provided by applicant): The overall objective of the proposed research is to define, at the level of chromatin regulation, a novel nuclear role of Wiskott-Aldrich syndrome protein (WASp) in the molecular and transcriptional pathways that program CD4 T cell (Th)1 differentiation and the development of type 1-pathogen-specific immunity. TBX21 gene encodes T-BET protein, the Th1-master regulator, which in concert with RUNX3 drives the activation of the target cytokine gene, IFNG. These activation events are important for specifying the Th1 cell fate. T cells from children with Wiskott-Aldrich syndrome (WAS), which lack expression of WASp, exhibit a concomitant deficiency of T-BET, fail to produce Th1-cytokine IFN, and develop severe systemic infections from intracellular pathogens, indicating a collective failure to develop a protective Th1-immune response. In contrast, there are indications that the Th2-response in a subset of WAS patients and in some murine models of WAS is pathologically exaggerated. Accordingly, the development of autoimmune colitis in some murine WAS model is Th2-cytokine-driven. Collectively, these observations suggests that an unbalanced activation of Th1 versus Th2 immunity may underlie the pathophysiology of WAS and its attendant complications. The specific objective for this application, therefore, is to understand WASp's role in the regulation of the Th1 network genes at a chromatin level, and clarify the molecular underpinnings of Th1-specific immune deficiency in human WAS. Using a combination of different biochemical approaches, we will delineate the protein:protein interactions of WASp in the Th1 cell genome (Aim1), test the role of WASp in local epigenetic modifications that favor productive transcription, and then identify perturbations in these regulatory events that may result from the absence of WASp (Aim 2) or from the presence of mutated WASp (Aim 3). These studies are expected to elucidate a previously unexplored, novel function of WASp in the epigenetic and transcriptional control of its target immune function genes in humans, and unearth an entirely new molecular basis for systemic immunodeficiency and the associated complications in the human WAS.
描述(由申请人提供):拟议研究的总体目标是在染色质调节水平上确定Wiskott-Aldrich综合征蛋白(WASp)在编程CD 4 T细胞(Th)1分化和1型病原体特异性免疫发展的分子和转录途径中的新型核作用。TBX 21基因编码T-BET蛋白,即Th 1主调节因子,其与RUNX 3协同驱动靶细胞因子基因IFNG的活化。这些活化事件对于指定Th 1细胞命运是重要的。来自Wiskott-Aldrich综合征(WAS)儿童的T细胞缺乏WASp表达,表现出T-BET的伴随缺陷,不能产生Th 1-细胞因子IFN,并发展出来自细胞内病原体的严重全身感染,表明集体未能发展保护性Th 1免疫应答。相反,有迹象表明,在一个子集的WAS患者和在一些鼠模型的WAS的Th 2-反应是病理夸大。因此,在一些鼠WAS模型中自身免疫性结肠炎的发展是Th 2-亮氨酸驱动的。总的来说,这些观察结果表明,一个不平衡的激活Th 1与Th 2免疫可能是基础的病理生理学的WAS及其伴随的并发症。因此,本申请的具体目标是了解WASp在染色质水平调节Th 1网络基因中的作用,并阐明人类WAS中Th 1特异性免疫缺陷的分子基础。使用不同的生物化学方法的组合,我们将描绘蛋白质:蛋白质相互作用的WASp在Th 1细胞基因组(Aim 1),测试WASp的作用,有利于生产性转录的局部表观遗传修饰,然后确定扰动这些监管事件,可能会导致从WASp(Aim 2)的情况下,或从突变的WASp(Aim 3)的存在。这些研究有望阐明WASp在人类靶免疫功能基因的表观遗传和转录控制中的一种以前未探索的新功能,并为人类WAS中的系统性免疫缺陷及其相关并发症挖掘出全新的分子基础。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
R-loops cause genomic instability in T helper lymphocytes from patients with Wiskott-Aldrich syndrome.
R环引起Wiskott-Aldrich综合征患者的T辅助淋巴细胞的基因组不稳定性。
- DOI:10.1016/j.jaci.2017.11.023
- 发表时间:2018-07
- 期刊:
- 影响因子:0
- 作者:Sarkar K;Han SS;Wen KK;Ochs HD;Dupré L;Seidman MM;Vyas YM
- 通讯作者:Vyas YM
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YATIN M VYAS其他文献
YATIN M VYAS的其他文献
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{{ truncateString('YATIN M VYAS', 18)}}的其他基金
Defining WASp-dependent pathways in replication stress
定义复制应激中的 WASp 依赖性途径
- 批准号:
10708353 - 财政年份:2023
- 资助金额:
$ 37.75万 - 项目类别:
Mechanisms of R loop-mediated genome instability in Wiskott-Aldrich syndrome
Wiskott-Aldrich 综合征中 R 环介导的基因组不稳定性的机制
- 批准号:
10333324 - 财政年份:2020
- 资助金额:
$ 37.75万 - 项目类别:
Mechanisms of R loop-mediated genome instability in Wiskott-Aldrich syndrome
Wiskott-Aldrich 综合征中 R 环介导的基因组不稳定性的机制
- 批准号:
10576354 - 财政年份:2020
- 资助金额:
$ 37.75万 - 项目类别:
Epigenetic Regulation by WASP of Human TBX21 Gene Transcription Program
WASP 对人类 TBX21 基因转录程序的表观遗传调控
- 批准号:
8698537 - 财政年份:2011
- 资助金额:
$ 37.75万 - 项目类别:
Epigenetic Regulation by WASP of Human TBX21 Gene Transcription Program
WASP 对人类 TBX21 基因转录程序的表观遗传调控
- 批准号:
8104742 - 财政年份:2011
- 资助金额:
$ 37.75万 - 项目类别:
Epigenetic Regulation by WASP of Human TBX21 Gene Transcription Program
WASP 对人类 TBX21 基因转录程序的表观遗传调控
- 批准号:
8321979 - 财政年份:2011
- 资助金额:
$ 37.75万 - 项目类别:
Molecular Pathogenesis of Immune Dysfunction In Wiskott-Aldrich-Syndrome
Wiskott-Aldrich 综合征免疫功能障碍的分子发病机制
- 批准号:
7522650 - 财政年份:2008
- 资助金额:
$ 37.75万 - 项目类别:
Molecular Pathogenesis of Immune Dysfunction In Wiskott-Aldrich-Syndrome
Wiskott-Aldrich 综合征免疫功能障碍的分子发病机制
- 批准号:
7626001 - 财政年份:2008
- 资助金额:
$ 37.75万 - 项目类别:
THE ROLE OF NUCLEAR WASP IN THE TRANSCRIPTIONAL REGULATION OF TH1 DIFFERENTIATION
核黄蜂在 TH1 分化转录调控中的作用
- 批准号:
7684118 - 财政年份:2008
- 资助金额:
$ 37.75万 - 项目类别:
Molecular Pathogenesis of Immune Dysfunction In Wiskott-Aldrich-Syndrome
Wiskott-Aldrich 综合征免疫功能障碍的分子发病机制
- 批准号:
7808040 - 财政年份:2008
- 资助金额:
$ 37.75万 - 项目类别:
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