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: 6602392
• 负责人: SUNG-YUN PAI
• 金额: $ 8.44万
• 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/6602392
• 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 因素，在免疫发育中起着两个核心作用。首先，有必要 用于T淋巴谱系的发展。其次，它指导差异化 T型辅助2型淋巴细胞（Th2细胞）的摄入，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 在过敏，哮喘和寄生虫感染中。因为rag-chimeric gata3-- 缺乏小鼠在T细胞发育中有一个非常早的障碍，几乎没有IS 关于体内GATA3功能的知名度。同样，gata3的机制 诱导Th2细胞因子的产生尚不清楚。我们假设1）GATA3 在胸腺细胞发育，成熟的T细胞迁移和 维持Th2表型； 2）GATA3具有独特的结构 生产特定细胞因子所需的成分。我们 在AIM 1中提出以生成有条件缺陷GATA3的鼠标的建议 仅在双阳性胸腺细胞阶段且缺乏T细胞 GATA3和四环素反应表达的转基因小鼠。使用 条件敲除和转基因模型我们将研究GATA3的作用 在胸腺细胞发育中，TT2的成熟T细胞迁移和维持 表型。用其他GATA因素替换可以使我们深入了解 定义GATA3功能的唯一和共享域。我们有初步 数据，使用体外和体内替代实验，这是不同的 GATA3的结构域对于生产IL-4，IL-5和 IL-13。在AIM 2中，我们描述了这些数据将如何指导我们对 DNA结合，蛋白质表达水平，GATA3的乙酰化的作用， 诱导其他TH2转录因子，但尚未发现的伙伴 GATA3在Th2细胞因子生产机理中的。 GATA3在 体内和体外对Th2介导的治疗具有重要意义 诸如过敏，哮喘和对寄生虫感染的反应等疾病。