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: 7157624
• 负责人: CRISTIANA STELLATO
• 金额: $ 38.82万
• 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/7157624
• 关键词: 3' Untranslated Regions; 5' -AMP-activated protein kinase; Ablation; Affect; Allergic; Antibodies; Binding; Biological Process; Cells; Chronic; Complex; Cytoplasm; Data; Disease; Elements; Enzymes; Eotaxin; Epithelial Cells; Event; Gene Expression; Gene Expression Regulation; Gene Transfer; Genes; Genetic Transcription; Human; Hypersensitivity; IL8 gene; Immune response; Immunity; Immunoprecipitation; Inflammation; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-3; Interleukin-4; Light; Link; Lung Inflammation; Malignant Neoplasms; Mediating; Mediator of activation protein; Messenger RNA; Metabolic Diseases; Methodology; Monitor; Numbers; Output; Pathogenesis; Pathway interactions; Peripheral Blood Mononuclear Cell; Process; Production; Protein Overexpression; Proteins; Protocols documentation; Publishing; RNA; RNA Processing; RNA Stability; RNA-Binding Proteins; Regulation; Reporting; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Stimulus; T-Lymphocyte; Testing; Transcript; Transcriptional Activation; base; beta-Chemokines; cytokine; in vivo; indexing; inhibitor/antagonist; messenger ribonucleoprotein; mouse model; novel; programs; response

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（mRNA）周转是基因表达的重要调控成分，其与转录激活合作提供响应于许多生物过程（包括免疫应答的激活）的快速适应性变化。这种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稳定性的增加决定性地调节免疫和炎症中几个关键基因的表达。我们发现，在人气道上皮细胞中由IL-4和TNF α触发的CC趋化因子嗜酸细胞活化趋化因子的产生依赖于嗜酸细胞活化趋化因子mRNA的稳定，并且该过程涉及胡萝卜素诱导的HuR与嗜酸细胞活化趋化因子mRNA的3 'UTR的结合。我们收集了进一步的数据，指出HuR是过敏反应中其他相关基因转录后调控的重要介质。在此基础上，我们假设，在慢性过敏性炎症部位的细胞因子环境可以通过激活HuR来改变炎症转录本的适当和及时的降解，HuR介导多种转录本的异常稳定，并最终增加促炎蛋白的产生。总的来说，我们的研究试图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）HuR在气道上皮细胞和T淋巴细胞中协调调节的靶mRNA集是什么（Aim 1）; 2）炎症信号激活HuR介导的功能的途径是什么（Aim 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）。提出的研究可以揭示HuR在协调过敏性炎症相关效应子亚组表达中的作用，可以揭示以前未被识别的控制这些基因转录后调控的信号通路，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。