CONTROL OF LINEAGE COMMITMENT IN DEVELOPING THYMOCYTES

胸腺细胞发育中谱系定型的控制

• 批准号: 6632000
• 负责人: Dietmar J Kappes
• 金额: $ 32.51万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632000
• 关键词: CD4 molecule; CD8 molecule; MHC class I antigen; MHC class II antigen; T cell receptor; biological signal transduction; cell differentiation; cytokine; cytotoxic T lymphocyte; flow cytometry; gene mutation; genetic mapping; genetic transcription; genetically modified animals; helper T lymphocyte; laboratory mouse; molecular cloning; thymus

The general aim of this project is to define the molecular basis of alternative commitment to the CD4 and CD8 T cell lineages during thymic development. A spontaneous autosomal recessive mutation has been identified in mice that specifically abrogates development of the CD4 T cell lineage causing a peripheral helper T cell deficiency ("helper deficient," or HD mice). Mutations at the CD4 and class II loci are specifically excluded as the cause of the phenotype, indicating that it represents a novel gene defect. The HD defect is transferred with cells of the hematopoietic lineage, and appears to be intrinsic to developing thymocytes. The current proposal addresses the following specific questions with regard to HD mice: 1) What are the developmental fates of class I- and II-restricted thymocytes in HD mice?, 2) Is the HD phenotype caused by a defect in stage- specific transcriptional regulation of the CD4 gene?, 3) Is mature T cell function impaired in HD mice, and if so is this due to alterations in TCR repertoire, T cell subset distribution or TCR-mediated signalling?, 4) What is the specific gene defect in HD mice? The proposed detailed phenotypic characterization of this unique mutant mouse and identification of the specific gene defect involved are expected to provide significant insights into the molecular mechanisms underlying lineage commitment.

该项目的总体目标是确定胸腺发育过程中 CD4 和 CD8 T 细胞谱系的替代承诺的分子基础。 在小鼠中发现了一种自发的常染色体隐性突变，该突变特异性地消除了 CD4 T 细胞谱系的发育，导致外周辅助 T 细胞缺陷（“辅助缺陷”或 HD 小鼠）。 CD4 和 II 类基因座的突变被明确排除为该表型的原因，表明它代表了一种新的基因缺陷。 HD 缺陷随造血谱系细胞转移，并且似乎是发育中的胸腺细胞所固有的。 目前的提案解决了有关 HD 小鼠的以下具体问题：1) HD 小鼠中 I 类和 II 类限制性胸腺细胞的发育命运是什么？，2) HD 表型是由 CD4 基因的阶段特异性转录调控缺陷引起的吗？，3) HD 小鼠中成熟 T 细胞功能是否受损，如果是的话，这是由于 TCR 库、T 细胞亚群的改变 分布或 TCR 介导的信号传导？, 4) HD 小鼠的具体基因缺陷是什么？所提出的这种独特突变小鼠的详细表型特征和所涉及的特定基因缺陷的鉴定预计将为谱系定型背后的分子机制提供重要的见解。