Effector cell gene regulation by Egr factors

Egr因子对效应细胞基因的调控

• 批准号: 6948559
• 负责人: ROBIN D HATTON
• 金额: $ 9.98万
• 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/6948559
• 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）： 从初始CD4+T细胞分化为具有不同细胞因子表达谱的Th1和Th2效应子亚群对于对抗原攻击产生适当且有效的反应至关重要。虽然Th1和Th2细胞发育的范例已被广泛认可，但驱动该过程的分子机制尚未完全了解。除了每个子集产生的标志性细胞因子外，Fas 配体（CD95L、FasL）的表达已被证明仅限于 Th1 细胞，因此是开始研究 CD4+ T 细胞表型发育基础的合适主题。已证明 NF-AT 和早期生长反应 (Egr) 家族的成员对于 FasL 的最大激活诱导表达很重要，尽管每个成员对最佳表达的贡献程度尚不清楚。还表明表达FasL的Th1细胞缺乏Egr-3的表达，而在FasL缺陷的Th2细胞中很容易检测到Egr-3的表达。要测试的假设是，Egr 和 NF-AT 家族成员直接作用于 FasL 启动子的协作相互作用是最佳表达所必需的，并且 Egr-3 可以作为竞争性调节因子发挥作用，抑制 FasL 表达。更广泛的假设基于 FasL 转录调控模型中 Th1 和 Th2 细胞中 Egr-3 的差异表达，认为 Egr 因子在效应 T 细胞亚群的生成中发挥着关键作用。具体目标将集中于证明 Egr 和 NF-AT 家族成员直接作用于 FasL 启动子的合作相互作用是最佳 FasL 表达所必需的，Egr-3 在 FasL 表达方面具有 Egr-3 的负调控特性， Egr 因子参与 Th1 和 Th2 子集的发育。