Effector cell gene regulation by Egr factors

Egr因子对效应细胞基因的调控

• 批准号: 7121676
• 负责人: ROBIN D HATTON
• 金额: $ 10.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2008-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121676
• 关键词: RNA interference; cell differentiation; chromatin immunoprecipitation; cyclosporines; developmental genetics; developmental immunology; gene expression; gene expression profiling; genetic promoter element; genetic regulation; genetic transcription; genetically modified animals; helper T lymphocyte; intermolecular interaction; laboratory mouse; microarray technology; nucleic acid probes; transcription factor

DESCRIPTION (provided by applicant): The differentiation from naive CD4+ T cells into Thl and Th2 effector subsets having distinct cytokine expression profiles is crucial to mounting an appropriate and effective response to antigenic challenge. While the paradigm of Thl and Th2 cell development is widely acknowledged, the molecular mechanisms driving this process are incompletely understood. In addition to the signature cytokines that each subset produce, the expression of Fas ligand (CD95L, FasL) has been demonstrated to be limited to Thl cells and therefore is an appropriate subject to begin to study the basis of CD4+ T cell phenotype development. It has been demonstrated that members of the NF-AT and early growth response (Egr) families are important for maximal activation-induced expression of FasL, though in what capacity each member contributes to optimal expression is unknown. It has also been shown that FasL-expressing Thl cells lack expression of Egr-3 whereas Egr-3 expression is easily detected in FasL-deficient Th2 cells. The hypothesis to be tested is that a cooperative interaction of Egr and NF-AT family members acting directly at the FasL promoter is required for optimal expression and that Egr-3 can function as a competitive regulator, suppressing FasL expression. A broader hypothesis, founded on the differential expression of Egr-3 in Thl and Th2 cells in the FasL transcriptional regulation model, posits that Egr factors play a pivotal role in the generation of effector T cell subsets. The specific aims will focus on demonstrating that a cooperative interaction of Egr and NF-AT family members acting directly at the FasL promoter is required for optimal FasL expression, that Egr-3 has negative regulatory properties of Egr-3 with respect to FasL expression, and that Egr factors are involved in Thl and Th2 subset development.

描述（由申请人提供）： 从幼稚的CD4+ T细胞中分化为具有不同细胞因子表达谱的Thl和Th2效应子集，对于安装对抗原挑战的适当有效反应至关重要。尽管广泛认识到THL和TH2细胞发育的范式，但驱动该过程的分子机制却尚不完全理解。除了每个子集产生的特征性细胞因子外，已经证明FAS配体（CD95L，FASL）的表达仅限于THL细胞，因此是开始研究CD4+ T细胞表型发育的基础的合适受试者。已经证明，NF-AT和早期生长反应（EGR）家族的成员对于最大激活诱导的FASL表达很重要，尽管每个成员以哪些能力有助于最佳表达。还已经表明，表达FASL的THL细胞缺乏EGR-3的表达，而在缺乏FASL的TH2细胞中很容易检测到EGR-3的表达。要检验的假设是，直接作用于FASL启动子的EGR和NF-AT家族成员的合作相互作用是最佳表达需要的，并且EGR-3可以作为竞争性调节剂起作用，从而抑制FASL表达。在FASL转录调控模型中，基于在ThL和Th2细胞中EGR-3的差异表达建立的更广泛的假设，认为EGR因子在效应T细胞子集的产生中起关键作用。具体的目的将集中于证明直接在FASL启动子上作用的EGR和NF-AT家族成员的合作相互作用是最佳FASL表达所必需的，EGR-3具有EGR-3在FASL表达方面具有负调节性能，并且EGR-3与FASL表达相对于FASL表达，并且EGR-3与THL和THL和TH2子集合发育有关。