Translational control of GATA-3

GATA-3 的翻译控制

基本信息

批准号：
8416331
负责人：
JIM F Miller
金额：
$ 23.18万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8416331
关键词：
5&apos Untranslated Regions Activities of Daily Living Address Alleles Asthma CD4 Positive T Lymphocytes Clinical Data Development Disease Effector Cell Elements Eukaryotic Initiation Factors Family Family member Future GATA3 transcription factor Generations Goals Helper-Inducer T-Lymphocyte Human Indium Intervention Maps Mediating Messenger RNA Modality Modeling Molecular Molecular Target Nerve Tissue Pathway interactions Play Process Proteins RNA RNA Helicase Regulation Regulatory Element Ribosomes Role Scanning Signal Pathway Signal Transduction Structure T-Cell Activation T-Lymphocyte Testing Th2 Cells Tissues Transcript Translation Initiation Translational Regulation Translations Up-Regulation Work base cell type eIF-4B helicase human FRAP1 protein in vitro Assay melting member novel promoter research study response small molecule thymocyte transcription factor

项目摘要

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.

描述（由申请人提供）：CD4+ T细胞对TH2子集的分化取决于转录因子GATA-3，该因子通过多种机制促进TH2分化。 GATA-3的表达和功能能力都是严格调节的过程，功能性GATA-3蛋白水平的小变化对细胞分化有重大影响。我们最近发现，通过选择性上调GATA-3翻译速率，TCR信号在GATA-3表达和随后的TH2分化中起着至关重要的作用。 GATA-3的这种翻译上调取决于通过PI3K/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RNA二级结构介导的。这些观察结果表明了转化调节的模型，其中TCR信号传导增强了EIF2A解旋酶的活性，这是通过5'UTR具有稳定的二级结构进行核糖体扫描所必需的。该提案的总体目的是绘制GATA-3 5'UTR中的顺式元素，并确定调节GATA-3翻译速率的下游信号通路。这些研究的总体目标是确定对GATA-3内的特定分子靶标，这些靶标会影响Th2效应细胞的产生和稳定性，并可以发展为实验模态，以控制包括哮喘在内的特应性疾病。