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FOXP3 Regulates RNA Alternative Splicing in Tregs

FOXP3 调节 Tregs 中的 RNA 选择性剪接

基本信息

批准号：
8822467
负责人：
BAOHUA ZHOU
金额：
$ 19.5万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8822467
关键词：
Affect Allergic Disease Alternative Splicing Antigens Asthma Autoimmune Diseases Autoimmune Process Autoimmunity Binding Biological Assay Cell physiology Cells Colitis Data Development Disease Exons Gene Targeting Genes Genetic Transcription Goals Hereditary Disease Heterogeneous-Nuclear Ribonucleoproteins Homeostasis Human Human Genetics Hypersensitivity Immune Immune response Immune system Immunoprecipitation In Vitro Inflammation Inflammatory Learning Lymphocyte Function Lymphocyte antigen Mediating Messenger RNA Molecular Pattern Phenotype Physiological Play Point Mutation Polyadenylation Prevention Process Proteins RNA RNA Splicing Regulation Regulatory T-Lymphocyte Role T cell differentiation T-Cell Development Testing Transcript Transcription Repressor/Corepressor Transcriptional Regulation Transfection Translational Regulation Yeasts base design early onset in vivo mRNA Precursor programs public health relevance response screening transcription factor yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Transcription factor FOXP3 is essential to establish a functional regulatory T cell (Treg) phenotype. Detailed studies have demonstrated that FOXP3 and interacting proteins reinforce their own expression, and activate the downstream FOXP3-dependent transcriptional program. In the preliminary data for this application, we show that FOXP3 directly interacts with hnRNPF (heterogeneous nuclear ribonucleoprotein F) to modulate hnRNPF-mediated RNA alternative splicing. In an immune response, wide spread changes in splicing patterns regulate lymphocyte function and responses to antigen. We hypothesize that FOXP3 modulates Treg development and function through modulating hnRNPF-mediated RNA alternative splicing. We will test this hypothesis with the following specific aims: 1. Define the mechanism for FOXP3 in modulating mRNA alternative splicing through its interaction with hnRNPF. 2. Define the ability of hnRNPF to modulate Treg differentiation and immune-mediated inflammation. Our overall goal for this application is to define, at the molecular level, how interaction between FOXP3 and hnRNPF affects hnRNPF's ability to bind to and modulate RNA alternative splicing. We will also define the effects of perturbed hnRNPF expression on Treg differentiation and function in autoimmune colitis. The information learned from these studies will provide a greater understanding of the role of FOXP3 in Treg differentiation and function, and how altered alternative splicing in Tregs affects immune-mediated inflammatory diseases.

描述（由申请人提供）：转录因子 FOXP3 对于建立功能性调节性 T 细胞 (Treg) 表型至关重要。详细的研究表明，FOXP3 和相互作用的蛋白增强了自身的表达，并激活下游 FOXP3 依赖性转录程序。在该应用的初步数据中，我们表明 FOXP3 直接与 hnRNPF（异质核核糖核蛋白 F）相互作用，调节 hnRNPF 介导的 RNA 选择性剪接。在免疫反应中，剪接模式的广泛变化调节淋巴细胞功能和对抗原的反应。我们假设 FOXP3 通过调节 hnRNPF 介导的 RNA 选择性剪接来调节 Treg 的发育和功能。我们将通过以下具体目标来检验这一假设： 1. 定义 FOXP3 通过与 hnRNPF 相互作用调节 mRNA 选择性剪接的机制。 2. 定义hnRNPF调节Treg分化和免疫介导的炎症的能力。我们此应用的总体目标是在分子水平上定义 FOXP3 和 hnRNPF 之间的相互作用如何影响 hnRNPF 结合和调节 RNA 选择性剪接的能力。我们还将定义 hnRNPF 表达紊乱对自身免疫性结肠炎 Treg 分化和功能的影响。从这些研究中获得的信息将有助于更好地了解 FOXP3 在 Treg 分化和功能中的作用，以及 Tregs 中可变剪接的改变如何影响免疫介导的炎症性疾病。