Translational control of GATA-3

描述（由申请人提供）：CD 4 + T细胞分化为Th 2亚群依赖于转录因子加塔-3，其通过多种机制促进Th 2分化。加塔-3的表达和功能能力都是严格调节的过程，功能性加塔-3蛋白水平的微小变化可对细胞分化产生显著影响。我们最近发现TCR信号通过选择性上调加塔-3翻译速率在诱导加塔-3表达和随后的Th 2分化中起关键作用。这种加塔-3的翻译上调依赖于通过PI 3 K/mTOR途径的TCR信号传导，我们的初步数据表明这是通过5 'UTR内的RNA二级结构介导的。这些观察结果表明了一种翻译调控模型，其中TCR信号传导增强了eIF 2A解旋酶的活性，这是核糖体扫描通过具有稳定二级结构的5 'UTR所必需的。本研究的总体目标是定位加塔-3 5 'UTR中的顺式元件，并鉴定调控加塔-3翻译速率的下游信号通路。这些研究的总体目标将是确定加塔-3中影响Th 2效应细胞的产生和稳定性的特定分子靶点，并且可以开发成控制特应性疾病（包括哮喘）的实验模式。

DESCRIPTION (provided by applicant): The differentiation of CD4+ T cells into the Th2 subset is dependent on the transcription factor GATA-3, which promotes Th2 differentiation through multiple mechanisms. Both the expression and functional capacity of GATA-3 are tightly regulated processes and small changes in the level of functional GATA-3 protein can have significant effects on cellular differentiation. We have recently discovered that TCR signaling plays a critical role in the induction of GATA-3 expression and subsequent Th2 differentiation through the selective upregulation of GATA-3 translation rate. This translational upregulation of GATA-3 is dependent on TCR signaling through the PI3K/mTOR pathway and our preliminary data indicate that this is mediated through RNA secondary structure within the 5'UTR. These observations suggest a model of translational regulation where TCR signaling enhances the activity of the eIF2A helicase, which is required for ribosome scanning through 5'UTR with stable secondary structures. The overall aims of this proposal are to map the cis element in the GATA-3 5'UTR and to identify the downstream signaling pathways that regulate GATA-3 translation rate. The overall goal of these studies will be to identify specific molecular targets within GATA-3 that impact on the generation and stability of Th2 effectors cells and that could be developed into experimental modalities to control atopic diseases, including asthma.