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: 7369904
• 负责人: MARK H KAPLAN
• 金额: $ 31.71万
• 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/7369904
• 关键词: Allergic; Asthma; Attenuated; B-Lymphocytes; CD4 Positive T Lymphocytes; Chimera organism; Complementary DNA; Development; Disease; Family; Gene Targeting; Goals; Helper-Inducer T-Lymphocyte; Hematopoietic; Hypersensitivity; In Vitro; Inflammation; Mature T-Lymphocyte; Mediating; Modeling; Mus; Mutant Strains Mice; Pattern; Phenotype; Population; Population Decreases; Principal Investigator; Proteins; Regulation; Retroviral Vector; Role; SPI1 gene; T-Cell Development; T-Lymphocyte; Th1 Cells; Th2 Cells; cytokine; in vivo; macrophage; mast cell; mouse model; mutant; neutrophil; programs; research study; response; 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是一种ETS家族转录因子，其对于多种造血谱系（包括巨噬细胞、B细胞、肥大细胞和中性粒细胞）的发育至关重要。PU.1缺陷型小鼠中的T细胞发育减弱，并且早期致死性以及在多种嵌合体模型中不能产生PU.1缺陷型T细胞阻碍了PU.1在成熟T细胞中的作用的分析。PU.1表达模式通常与加塔家族因子相反。由于GATA3表达在T辅助细胞发育过程中受到调节，我们研究了T辅助细胞亚群中的PU.1表达。与先前的观察结果相矛盾的是，PU. 1在T细胞中不表达，我们观察到PU. 1在Th2细胞中表达，但在Th1细胞中不表达。引人注目的是，PU.1在具有特定Th2细胞因子的低表达的Th2培养物群体中表达。此外，PU.1在Th2群体中的逆转录病毒表达降低了Th2细胞因子的分泌。初步实验表明，PU.1可能通过干扰GATA 3功能来调节Th2表型。本申请的目的是确定PU.1在Th2调节中的作用，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。我们将通过检查PU.1基因靶向小鼠并通过评估体外和体内T辅助细胞群体发育来确定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GATA 3和其他Th2调节因子的功能。我们已经确定PU.1作为Th2限制性负调节因子的Th2细胞因子分泌。PU.1表达和功能的调节可以作为治疗Th2介导的疾病，包括哮喘和过敏症。