FOXP3 Regulates RNA Alternative Splicing in Tregs

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和相互作用的蛋白质增强了自身的表达，并激活了下游FOXP3依赖的转录程序。在本申请的初步数据中，我们表明FOXP3直接与hnRNPF（异质核核糖核蛋白F）相互作用，以调节hnRNPF介导的RNA选择性剪接。在免疫应答中，剪接模式的广泛变化调节淋巴细胞功能和对抗原的应答。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。我们将测试这一假设与以下具体目标：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。本申请的总体目标是在分子水平上确定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。我们还将确定干扰hnRNPF表达对自身免疫性结肠炎中Treg分化和功能的影响。从这些研究中了解到的信息将提供对FOXP3在Treg分化和功能中的作用的更好理解，以及TcG中改变的选择性剪接如何影响免疫介导的炎症性疾病。

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.