The role of PU.1 in T helper 2 function

PU.1在T helper 2功能中的作用

• 批准号: 7027626
• 负责人: MARK H KAPLAN
• 金额: $ 33.29万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027626
• 关键词: atopy; cell population study; cytokine; developmental genetics; developmental immunology; gene expression; genetically modified animals; helper T lymphocyte; inflammation; laboratory mouse; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): PU.1 is an ETS family transcription factor that is crucial for the development of multiple hematopoietic lineages including macrophages, B cells, mast cells and neutrophils. T cell development in PU.1-deficient mice is attenuated and the early lethality as well as the inability to generate PU.1-deficient T cells in multiple chimera models has hampered the analysis of the role of PU.1 in mature T cells. PU.1 expression patterns often appear opposite that of GATA family factors. Since GATA3 expression is modulated during T helper cell development, we investigated PU.1 expression in T helper subsets. Contradicting previous observations that PU.1 is not expressed in T cells, we observed PU.1 expression in Th2 cells but not in Th1 cells. Strikingly, PU.1 is expressed in populations of Th2 cultures that have low expression of particular Th2 cytokines. Furthermore, retroviral expression of PU.1 in Th2 populations decreases secretion of Th2 cytokines. Preliminary experiments suggest that PU.1 may regulate the Th2 phenotype by interfering with GATA3 function. The goal of this application is to define the role of PU.1 in Th2 regulation and to elucidate the mechanism of interference with the development of the Th2 phenotype. Our hypothesis is that PU.1 is an important regulator of Th2 function. We will investigate this issue by examining PU.1 gene targeted mice and determining the Th2 phenotype by assessing both in vitro and in vivo T helper cell population development. We will also examine the structural requirements for PU.1 function in Th2 cells and how PU.1 may regulate GATA3 and other Th2-regulating factor function. We have identified PU.1 as a Th2-restricted negative regulatory factor of Th2 cytokine secretion. Regulation of PU.1 expression and function could be manipulated as a treatment for Th2 mediated diseases including asthma and allergies.

描述（由申请人提供）：PU.1是ETS家族转录因子，对包括巨噬细胞、B细胞、肥大细胞和中性粒细胞在内的多种造血谱系的发展至关重要。PU.1缺陷小鼠的T细胞发育减弱，在多个嵌合体模型中，PU.1缺陷小鼠的早期致死率以及不能产生PU.1缺陷T细胞阻碍了对PU.1在成熟T细胞中的作用的分析。PU.1的表达模式往往与GATA家族因子相反。由于GATA3的表达在辅助性T细胞发育过程中被调节，我们研究了PU.1在辅助性T细胞亚群中的表达。与之前观察到的PU.1在T细胞中不表达相反，我们观察到PU.1在Th2细胞中表达，而在Th1细胞中不表达。引人注目的是，PU.1在特定Th2细胞因子低表达的Th2培养群体中表达。此外，在Th2群体中，PU.1的逆转录病毒表达会减少Th2细胞因子的分泌。初步实验表明，PU.1可能通过干扰GATA3功能调控Th2表型。本应用的目的是确定PU.1在Th2调控中的作用，并阐明干扰Th2表型发展的机制。我们的假设是PU.1是Th2功能的重要调节因子。我们将通过检测PU.1基因靶向小鼠，并通过评估体外和体内T辅助细胞群发育来确定Th2表型来研究这个问题。我们还将研究PU.1在Th2细胞中功能的结构要求，以及PU.1如何调节GATA3和其他Th2调节因子的功能。我们已经确定PU.1是Th2限制的Th2细胞因子分泌的负调节因子。调控PU.1的表达和功能可以作为治疗Th2介导的疾病，包括哮喘和过敏。