Extrathymic T cell precursors: commitment and efficacy
胸腺外 T 细胞前体:承诺和功效
基本信息
- 批准号:7529944
- 负责人:
- 金额:$ 39.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-01-01 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAftercareBloodBlood CellsBone MarrowBone Marrow TransplantationCell LineageCellsClinicalCommitConditionCytotoxic agentDependenceDependencyDevelopmentGene ExpressionGene Expression RegulationGenerationsGenesGenetic TranscriptionGoalsHome environmentHomingHourImmigrantImmune systemIn VitroInfectionInjection of therapeutic agentLymphoidLymphoid CellLymphopoiesisMATK geneMalignant NeoplasmsMolecular AnalysisMusMyelogenousNatural regenerationNatureNormal CellPTPRC genePathway interactionsPhenotypeProceduresProto-Oncogene Protein c-kitPublic HealthRangeReporter GenesStagingStem cellsSurfaceT-Cell DepletionT-LymphocyteThymus Glandcomparativein vivoirradiationnotch proteinprogenitorprototypereconstitutionresearch studyself-renewal
项目摘要
DESCRIPTION (provided by applicant): The nature of thymus immigrants that contribute most effectively to T lymphopoiesis is unknown even though several well-characterized progenitors have been described. Some of these cells can give rise to lymphoid and non-lymphoid lineages, others are lymphoid-restricted and yet others are T lymphoid lineage-restricted. Cells with T lineage-restricted potential, circulating T cell progenitors (CTP), have recently been described in the blood with the aid of a pre-TCR1- controlled reporter gene. Here it is proposed to further phenotypically characterize CTP and their progeny and to analyze their efficacy in T cell generation and commitment to the T cell lineage in further detail. Furthermore, the Notch dependence of T lineage commitment will be addressed in mice with reversible inhibition of Notch-dependent transcription by analyzing the generation of cells with a CTP surface phenotype from precursors that are deficient in Notch- dependent transcription. Subsequently, after isolation of CTP and relieving the transcriptional block, the functional potential will be determined. Finally, gene expression of CTP will be compared with that of multipotent (LSK) and intrathymic (ETP) precursors in an attempt to place these cells in a differentiation pathway. Special emphasis will be given to gene regulation by the LRF gene that antagonizes Notch in early precursors of lymphoid cells. In a second aim, the efficacy of several well-characterized extrathymic precursors to generate T cells will be compared by depleting such precursors prior to injecting bone marrow or blood cells into Il-7ra- deficient recipients. In additional studies lineage fate tracing by IL-7R1-cre will be used to determine the contribution of IL-7R1-expressing precursors to intrathymic precursors such as ETP. Furthermore, the short-term potential of cells to home to the thymus will be compared 24 hours after injection of cells by explanting intrathymic donor-derived cells under conditions of limiting dilution into cultures containing OP9-DL1 feeder cells. Once information on different precursors with either multipotential (prototype LSK), lymphoid-restricted potential (prototype CLP) or T lineage-restricted potential (prototype CTP) has been established these subsets will be further subdivided by already established markers in order to pinpoint the most relevant precursors as precisely as possible. Overall this project aims at establishing mechanisms of extrathymic T lineage commitment as well as identifying the most potent extrathymic precursors for T lymphopoiesis. PUBLIC HEALTH RELEVANCE: This project aims at the identification and characterization of the most effective cells in bone marrow and blood that under different conditions permit the reconstitution of the T cell immune system that protects from infection and malignancy. Identification of the extrathymic T cell precursors will help in the faster regeneration of the immune system after treatment of malignancy by x- irradiation and/or cytotoxic drugs that result in T cell depletion.
描述(由申请人提供):尽管已经描述了几种具有良好特征的祖细胞,但对T淋巴生成最有效的胸腺移植物的性质尚不清楚。这些细胞中的一些可以产生淋巴细胞和非淋巴细胞谱系,另一些是淋巴细胞限制性的,还有一些是T淋巴细胞限制性的。具有T谱系限制电位的细胞,循环T细胞祖细胞(CTP),最近在tcr1前控制的报告基因的帮助下在血液中被描述。在这里,我们建议进一步表征CTP及其后代,并进一步详细分析它们在T细胞生成中的功效和对T细胞谱系的承诺。此外,通过分析缺乏Notch依赖性转录的前体产生具有CTP表面表型的细胞,将在具有Notch依赖性转录可逆抑制的小鼠中解决T谱系承诺的Notch依赖性。随后,在分离CTP并解除转录阻滞后,将确定功能电位。最后,将CTP的基因表达与多能性(LSK)和胸腺内(ETP)前体进行比较,试图将这些细胞置于分化途径中。特别强调的是LRF基因在淋巴样细胞早期前体中拮抗Notch的基因调控。第二个目标是,在向缺乏Il-7ra的受体注射骨髓或血细胞之前,通过消耗这些前体来比较几种具有良好特征的胸腺外前体产生T细胞的功效。在其他研究中,IL-7R1-cre的谱系命运追踪将用于确定表达il - 7r1的前体对胸腺内前体(如ETP)的贡献。此外,在限制稀释的条件下,将胸腺内供体来源的细胞移植到含有OP9-DL1饲养细胞的培养物中,比较细胞在注射细胞24小时后返回胸腺的短期潜力。一旦建立了具有多电位(原型LSK)、淋巴细胞限制性电位(原型CLP)或T谱系限制性电位(原型CTP)的不同前体的信息,这些亚群将被已经建立的标记进一步细分,以便尽可能精确地查明最相关的前体。总体而言,本项目旨在建立胸腺外T谱系承诺的机制,并确定最有效的T淋巴生成的胸腺外前体。公共卫生相关性:该项目旨在鉴定和表征骨髓和血液中最有效的细胞,这些细胞在不同条件下允许T细胞免疫系统的重建,以防止感染和恶性肿瘤。胸腺外T细胞前体的鉴定将有助于在x射线照射和/或细胞毒性药物导致T细胞耗竭的恶性肿瘤治疗后免疫系统的更快再生。
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)
专利数量(0)
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HARALD VON BOEHMER其他文献
HARALD VON BOEHMER的其他文献
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{{ truncateString('HARALD VON BOEHMER', 18)}}的其他基金
Molecular Pathways in T Cell Development and T-ALL
T 细胞发育和 T-ALL 的分子途径
- 批准号:
7780947 - 财政年份:2010
- 资助金额:
$ 39.41万 - 项目类别:
Molecular Pathways in T Cell Development and Thymic Lymphoma
T 细胞发育和胸腺淋巴瘤的分子途径
- 批准号:
6989689 - 财政年份:2004
- 资助金额:
$ 39.41万 - 项目类别:
pTa-controlled reporter to identify lymphoid precursor
pTa 控制的报告基因识别淋巴前体
- 批准号:
7003715 - 财政年份:2003
- 资助金额:
$ 39.41万 - 项目类别:
pTa-controlled reporter to identify lymphoid precursor
pTa 控制的报告基因识别淋巴前体
- 批准号:
6690040 - 财政年份:2003
- 资助金额:
$ 39.41万 - 项目类别:
pTa-controlled reporter to identify lymphoid precursor
pTa 控制的报告基因识别淋巴前体
- 批准号:
6832872 - 财政年份:2003
- 资助金额:
$ 39.41万 - 项目类别:
Extrathymic T cell precursors: commitment and efficacy
胸腺外 T 细胞前体:承诺和功效
- 批准号:
8291226 - 财政年份:2003
- 资助金额:
$ 39.41万 - 项目类别:
Extrathymic T cell precursors: commitment and efficacy
胸腺外 T 细胞前体:承诺和功效
- 批准号:
8105057 - 财政年份:2003
- 资助金额:
$ 39.41万 - 项目类别:
pTa-controlled reporter to identify lymphoid precursor
pTa 控制的报告基因识别淋巴前体
- 批准号:
6572039 - 财政年份:2003
- 资助金额:
$ 39.41万 - 项目类别:
pTa-controlled reporter to identify lymphoid precursor
pTa 控制的报告基因识别淋巴前体
- 批准号:
7172234 - 财政年份:2003
- 资助金额:
$ 39.41万 - 项目类别:
Extrathymic T cell precursors: commitment and efficacy
胸腺外 T 细胞前体:承诺和功效
- 批准号:
7882652 - 财政年份:2003
- 资助金额:
$ 39.41万 - 项目类别:
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