RNA-binding Protein HuR in Allergic Inflammation

RNA 结合蛋白 HuR 在过敏性炎症中的作用

• 批准号: 7035894
• 负责人: CRISTIANA STELLATO
• 金额: $ 39.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035894
• 关键词: Adenoviridae; RNA binding protein; T lymphocyte; chemokine; clinical research; cytokine; disease /disorder model; gene expression; human subject; immunoprecipitation; inflammation; interleukin 13; interleukin 4; kinase inhibitor; laboratory mouse; messenger RNA; protein protein interaction; respiratory epithelium; respiratory hypersensitivity; ribonucleoproteins; serine threonine protein kinase; small interfering RNA; transfection /expression vector; tumor necrosis factor alpha

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.

信使RNA(Messenger RNA，mRNA)周转是基因表达的重要调节成分，它与转录激活协同作用，对许多生物过程做出快速适应性改变，包括免疫反应的激活。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稳定性的提高对免疫和炎症中的几个关键基因的表达起着关键的调节作用。我们发现在人的呼吸道上皮细胞中，由IL-4和TNFa触发的CC趋化因子eoaxin的产生依赖于eoaxin mRNA的稳定，这一过程涉及细胞因子诱导的Hur与eoaxin mRNA的3‘端非编码区的结合。我们收集了进一步的数据，指出HUR是变态反应中其他相关基因转录后调控的重要中介。在此基础上，我们假设慢性变态反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，从而介导多个转录物的异常稳定，最终导致促炎蛋白的产生增加。总体而言，我们的研究试图通过回答三个主要问题来测试Hur在慢性变态反应性炎症发病机制中的作用：1)Hur在呼吸道上皮细胞和T淋巴细胞中协调调节的靶向mRNAs的集合(目标1)；2)炎症信号激活Hur介导的功能的途径(目标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(目标3)。拟议中的研究可能揭示Hur在协调变态反应性炎症相关效应物的子集表达中的作用，可能揭示先前未知的控制这些基因转录后调控的信号通路，并最终确定Hur是一种调节分子，其局部抑制可能是治疗所需的。