GATA3 in T cell maturation/T helper cell differentiation

GATA3 在 T 细胞成熟/T 辅助细胞分化中的作用

• 批准号: 6725301
• 负责人: SUNG-YUN PAI
• 金额: $ 12.5万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6725301
• 关键词: T lymphocyte; acetylation; cell differentiation; cell migration; genetically modified animals; helper T lymphocyte; interleukin 13; interleukin 4; interleukin 5; laboratory mouse; protein biosynthesis; protein structure function; transcription factor

DESCRIPTION (provided by applicant): GATA3, a T cell-specific transcription factor, plays two central roles in immune development. First, it is necessary for the T lymphoid lineage development. Second, it directs the differentiation of T helper type 2 lymphocytes (Th2 cells) and induces the production of Th2 cytokines, such as IL-4, IL-5 and IL-13. Th2 cells mediate the immune response in allergy, asthma, and parasitic infection. Because RAG-chimeric GATA3- deficient mice have an extremely early block in T cell development, little is known about GATA3 function in vivo. Likewise, the mechanism by which GATA3 induces Th2 cytokine production remains unclear. We hypothesize that 1) GATA3 has essential functions in thymocyte development, mature T cell migration, and maintenance of the Th2 phenotype; and 2) GATA3 has distinct structural components that are required for the production of specific cytokines. We propose in Aim 1 to generate a mouse conditionally deficient in GATA3, such that only T cells at the double positive thymocyte stage and beyond lack GATA3, and a tetracycline-responsive GATA3-expressing transgenic mouse. Using the conditional knockout and transgenic models we will study the role of GATA3 in thymocyte development, mature T cell migration and maintenance of the Th2 phenotype. Substitution with other GATA factors can give us insight into the unique and shared domains that define GATA3 function. We have preliminary data, using substitution experiments in vitro and in vivo, that distinct structural domains of GATA3 are necessary for the production of IL-4, IL-5 and IL-13. In Aim 2, we describe how these data will guide our investigation of the role of DNA binding, protein expression level, acetylation of GATA3, induction of other Th2 transcription factors, and as yet undiscovered partners of GATA3 in the mechanism of Th2 cytokine production. The study of GATA3 in vivo and in vitro has important implications for the therapy of Th2-mediated disease such as allergy, asthma, and the response to parasitic infection.

描述（由申请人提供）：GATA3，T细胞特异性转录 因子，在免疫发育中发挥两个核心作用。首先，有必要 用于T淋巴谱系的发育。二是引导差异化 2 型辅助 T 淋巴细胞（Th2 细胞）并诱导 Th2 的产生 细胞因子，例如IL-4、IL-5和IL-13。 Th2细胞介导免疫反应 过敏、哮喘和寄生虫感染。因为RAG-嵌合GATA3- 缺陷小鼠的 T 细胞发育受到极早期的阻碍，但很少有 已知GATA3在体内的功能。同样，GATA3 的机制 诱导 Th2 细胞因子产生仍不清楚。我们假设 1) GATA3 在胸腺细胞发育、成熟 T 细胞迁移和 维持Th2表型； 2) GATA3具有独特的结构 产生特定细胞因子所需的成分。我们 在目标 1 中建议生成 GATA3 有条件缺陷的小鼠，例如 只有双阳性胸腺细胞阶段及以后的T细胞缺乏 GATA3，以及四环素反应性 GATA3 表达转基因小鼠。使用 条件敲除和转基因模型我们将研究GATA3的作用 胸腺细胞发育、成熟 T 细胞迁移和 Th2 维持 表型。用其他 GATA 因子替代可以让我们深入了解 定义 GATA3 功能的唯一和共享域。我们有初步的 数据，使用体外和体内替代实验，不同 GATA3 的结构域对于产生 IL-4、IL-5 和 IL-13。在目标 2 中，我们描述了这些数据将如何指导我们的调查 DNA 结合、蛋白质表达水平、GATA3 乙酰化的作用， 诱导其他 Th2 转录因子以及尚未发现的伙伴 GATA3 在 Th2 细胞因子产生机制中的作用。 GATA3的研究 体内和体外对 Th2 介导的治疗具有重要意义 过敏、哮喘等疾病以及对寄生虫感染的反应。