HuR in antigen-specific T cell activation and proliferation

HuR 在抗原特异性 T 细胞激活和增殖中的作用

基本信息

  • 批准号:
    9502705
  • 负责人:
  • 金额:
    $ 23.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-06-11 至 2020-05-31
  • 项目状态:
    已结题

项目摘要

Abstract The HuR (elavl1) family of RNA binding proteins (RBPs) posttranscriptionally regulates the expression of a number of pro-inflammatory genes involved in immunity, autoimmunity, and allergy. HuR binds to AU-rich elements (AREs) in 3' untranslated regions (UTRs) of labile mRNA transcripts to stabilize and recruit them to heavy polysomes. However, the mechanisms by which posttranscriptional gene regulation controls CD4+ T cell differentiation and activation are unclear, despite the fact that many pro-inflammatory factors such as cytokines and chemokines are regulated at this level by RBPs. Genome wide array analysis has identified multiple asthma related genes. However, such broad approaches may overlook relevant genes, as there is a poor correlation between steady-state mRNA levels and protein. In order to overcome these limitations, methods such as RNA immunoprecipitation applied either to microarrays or deep sequencing (RIP-Chip or RIP-Seq) have been developed. RIP-Seq identifies genes for which steady-state mRNA levels do not significantly change. The work herein proposed supports the long term goal of understanding posttranscriptional gene regulation in CD4+ T cell- mediated inflammation. The objective of this application, is to understand how HuR regulates key molecules involved in the activation and proliferation of CD4+ T cells during responses to antigen. The central hypothesis is that HuR is required for antigen-specific activation and proliferation of CD4+ T cells. The rationale for this proposal stems from reports demonstrating that HuR regulates Th2 cytokine production through stabilization of relevant mRNAs and is also important for Th2 differentiation. Preliminary results suggest that HuR plays a critical role in IL-2 homeostasis. IL-2 is one of the first cytokines made by T cells soon after activation. CD4+ T cells from OVA-immunized HuR KO mice also showed severe defects in antigen-specific proliferative responses. In an allergic airway inflammatory model, OVA-challenged HuR KO mice had decreased lung cellular infiltration. Understanding posttranscriptional mechanisms which govern T cell activation will allow the field to develop therapies to direct outcomes of inflammatory responses in multiple autoimmune diseases. Additionally, such knowledge can have broad implications to T cell biology in general. The central hypothesis will be tested and the proposal's objectives accomplished by the following two specific aims: 1) Determine the effect of HuR deletion on antigen-specific CD4+ T cell activation, 2) Define the mechanisms by which HuR deletion alters T cell function. The proposed study is innovative because using both RNA-Seq and RIP-Seq in concert will allow for identification of novel networks of HuR targets that are critical to normal antigen-specific responses. The research is significant because it will improve the field's understanding of posttranscriptional modulation of antigen-specific T cell activation and proliferation, as well as identifying HuR targets vital to allergic airway inflammation.
摘要 RNA结合蛋白(RBP)的HuR(elavl 1)家族转录后调节一个转录因子的表达。 参与免疫、自身免疫和过敏的促炎基因的数量。HuR与富含AU的 在不稳定的mRNA转录物的3'非翻译区(UTR)中的ARE元件(战神),以稳定和招募它们, 重多聚核糖体。然而,转录后基因调控控制CD 4 + T细胞的机制, 分化和激活尚不清楚,尽管许多促炎因子如细胞因子 而趋化因子在这个水平上受到限制性内切酶的调节。全基因组阵列分析确定了多发性哮喘 相关基因然而,这种广泛的方法可能会忽略相关基因,因为相关性很差 mRNA水平和蛋白质水平之间的关系。为了克服这些限制,RNA等方法 应用于微阵列或深度测序(RIP-Chip或RIP-Seq)的免疫沉淀已经被 开发RIP-Seq鉴定稳态mRNA水平不显著变化的基因。工作 本文提出的支持理解CD 4 + T细胞中转录后基因调控的长期目标, 介导的炎症。本申请的目的是了解HuR如何调节关键分子 在对抗原的应答过程中参与CD 4 + T细胞的活化和增殖。核心假设 HuR是CD 4 + T细胞的抗原特异性活化和增殖所必需的。这样做的理由 这项提议源于一些报告,这些报告表明HuR通过稳定Th 2细胞因子的产生来调节Th 2细胞因子的产生。 它是一种重要的基因,对Th 2分化也很重要。初步结果表明,HuR起着关键的作用, 在IL-2稳态中的作用。IL-2是T细胞活化后不久产生的第一批细胞因子之一。cd 4 + T细胞 OVA免疫的HuR KO小鼠也显示出抗原特异性增殖反应的严重缺陷。中 在过敏性气道炎症模型中,OVA攻击的HuR KO小鼠具有减少的肺细胞浸润。 理解T细胞活化的转录后机制将使该领域得到发展 在多种自身免疫性疾病的炎症反应的直接结果的治疗。此外,这样的 一般来说,知识对T细胞生物学具有广泛的影响。中心假设将得到检验, 建议的目标通过以下两个具体目标来实现:1)确定HuR删除的效果 2)确定HuR缺失改变T细胞功能的机制。 拟议的研究是创新的,因为同时使用RNA-Seq和RIP-Seq将允许识别 HuR靶点的新网络,这些靶点对正常的抗原特异性反应至关重要。这项研究具有重要意义 因为它将提高该领域对抗原特异性T细胞的转录后调节的理解, 活化和增殖,以及识别对过敏性气道炎症至关重要的HuR靶点。

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