RNA-binding Protein HuR in Allergic Inflammation

信使RNA （mRNA）的转换是基因表达的重要调控成分，它与转录激活合作，在响应许多生物过程（包括免疫反应的激活）时提供快速适应性变化。这一机制的失调越来越被认为是癌症和代谢紊乱等疾病的致病事件。mRNA稳定性的增加对免疫和炎症中几个关键基因的表达具有关键调控作用。我们发现，在人气道上皮细胞中，IL-4和TNFa触发CC趋化因子eotaxin的产生依赖于eotaxin mRNA的稳定，这一过程涉及细胞因子诱导的HuR与eotaxin mRNA的3'UTR的关联。我们收集了进一步的数据，指出HuR是过敏中其他相关基因转录后调控的重要媒介。在此基础上，我们假设慢性变应性炎症部位的细胞因子环境可以通过激活HuR来改变炎症转录物的适当和及时的降解，从而介导多种转录物的异常稳定，最终增加促炎蛋白的产生。总的来说，我们的研究旨在通过回答三个主要问题来测试HuR在慢性过敏性炎症发病机制中的作用：1)在气道上皮细胞和T淋巴细胞中，HuR协调调节的一组靶mrna是什么（Aim 1）；2)炎症信号激活hr介导功能的途径是什么（目的2）；3)在小鼠炎症模型中，调节HuR功能对炎症和HuR靶基因表达的影响（目的3）。所提出的研究可以揭示HuR在协调过敏性炎症相关效应子子集的表达中的作用，可以揭示以前未被识别的控制这些基因转录后调节的信号通路，并最终确定HuR作为一种调节分子，其局部抑制可能是治疗所需的。

Messenger RNA (mRNA) turnover is a crucial regulatory component of gene expression, that cooperate with transcriptional activation in providing rapid adaptive changes in response to many biological processes, including the activation of the immune response. The disregulation of this mechanism is increasingly recognized as a pathogenic event in diseases such as cancer and metabolic disorders. Increase in mRNA stability critically regulates the expression of several key genes in immunity and inflammation. We found that production of the CC chemokine eotaxin triggered by IL-4 and TNFa in human airway epithelial cells relies on the stabilization of the eotaxin mRNA, and that this process involves the cytokine-induced association of HuR to the 3'UTR of eotaxin mRNA. We gathered further data pointing at HuR as important mediator of posttranscriptional regulation of other relevant genes in allergy. On this basis, we hypothesize that the cytokine milieu at the site of chronic allergic inflammation could alter the proper and timely degradation of inflammatory transcripts by activating HuR, which mediate the aberrant stabilization of multiple transcripts and ultimately, the increased production of proinflammatory proteins. Overall, our research seeks to test the role of HuR in the pathogenesis of chronic allergic inflammation by answering three major questions: 1) what is the set of target mRNAs that HuR coordinately regulates in airway epithelial cells and T lymphocytes (Aim 1); 2) what are the pathways by which inflammatory signals activate HuR-mediated function (Aim 2); 3) what is the effect of modulating HuR function on inflammation and HuR target gene expression in a mouse model of inflammation (Aim 3). The studies proposed could uncover a role for HuR in coordinating the expression of a subset of relevant effectors of allergic inflammation, could reveal previously unrecognized signaling pathways governing the posttranscriptional regulation of these genes and ultimately identify HuR as a regulatory molecule whose local inhibition might be therapeutically desirable.