FOXP3 Regulates RNA Alternative Splicing in Tregs

描述(由申请人提供)：转录因子FOXP3是建立功能性调节性T细胞(Treg)表型所必需的。详细的研究表明，FOXP3和相互作用的蛋白增强了自己的表达，并激活了下游依赖FOXP3的转录程序。在这一应用的初步数据中，我们表明FOXP3直接与hnRNPF(异质性核糖核蛋白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通过调控hnRNPF介导的RNA选择性剪接来调控Treg的发育和功能。我们将通过以下具体目标来验证这一假说：1.确定FOXP3通过与hnRNPF相互作用来调节mRNA选择性剪接的机制。2.明确hnRNPF调节Treg分化和免疫介导炎症的能力。我们这一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与RNA选择性剪接的结合和调节能力。我们还将确定扰动的hnRNPF表达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使我们更好地理解FOXP3在Treg分化和功能中的作用，以及Treg中变化的选择性剪接如何影响免疫介导性炎症性疾病。

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.