Function of microRNA in pro-inflammatory gene expression

microRNA在促炎基因表达中的功能

• 批准号: 7539197
• 负责人: Jiahuai Han
• 金额: $ 46.47万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539197
• 关键词: 3' Untranslated Regions; Affect; Arthritis; Binding; Binding Proteins; Biochemical; Biological; Biological Process; Cells; Complex; Cytokine Gene; Data; Development; Disease; Drosophila genus; Elements; Family; Family member; Functional RNA; Future; Gene Expression; Gene Targeting; Genes; Genetic; Housekeeping; Human; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Interleukin-1; Interphase Cell; Life; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Molecular; Multiple Sclerosis; Paper; Physiological; Process; Production; RNA-Induced Silencing Complex; Regulation; Research; Research Personnel; Rheumatoid Arthritis; Role; Sepsis; Septic Shock; Signal Pathway; Small Interfering RNA; Stimulus; TIS11 protein; Trauma; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; base; cyclooxygenase 2; cytokine; genome wide association study; genome-wide; human DICER1 protein; interest; mRNA Decay; mRNA Stability; mRNA Transcript Degradation; member; novel; phrases; prevent; programs; response

Inflammation js the body's natural protective response to infection or injury, but abnormal or uncontrolled inflammatory responses can do more harm than good. A breakdown in the appropriate regulation of inflammation underlies a wide range of common diseases, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and septic shock. The expression of pro-inflammatory genes by cells in the immune system is the most crucial step in the development of inflammation. Although significant progress has been made, the mechanism of pro-inflammatory gene expression is still not fully understood. The long- term objective of this proposal is to gain an understanding of the regulation and function of microRNA (miRNA), a newly identified group of short non-coding single-stranded RNA, in the expression of pro- inflammatory genes. It is knownthat pro-inflammatory genes such as tumor necrosis factor, interleukin-1, arid cyclooxygenase 2 are controlled at multiple levels of gene expression, one of the most important of which is at the regulation of then- mRNAstability. Quick mRNAdegradation of these pro-inflammatorygenes serves as a mechanism to control the level of pro-inflammatory molecules. AU-rich elements (AREs) located in the 3' untranslated region of these short-lived mRNAs dictate their degradation. Ourrecent study revealed that Dicer and Argonaute (Ago/eif2C) family members, components involved in microRNA(miRNA) processing and function, are required for the rapid decay of mRNA that contain AREs (ARE-mRNA). Furthermore, we found miR16, a human miRNAwith a sequence that is partially complementaryto the ARE sequence, to be required for ARE-mRNAturnover. The requirement of miR16 in ARE-mRNA decay in resting cells suggests a physiological 'housekeeping' function of miR16 in which it prevents high basal levels of pro-inflammatory gene expression. This proposal outlines a study into the mechanism of miRNA-regulated cytokine gene expression, with an emphasis on how inflammatory stimuli induce stabilization of ARE-mRNA by blocking miRNA-mediated mRNA degradation. In this research plan, we will also evaluate the overall function of miR16 by genome-wide identifying and classifying of miR16-targeted genes. To achieve our aims, we will utilize a combination of genetic, biochemical, and molecular biological approaches. The work proposed in this application will contribute to a better understanding of pro-inflammatory gene expression. Understanding the function of miRNA in mRNA stability of pro-inflammatory genes should provide new avenues for developing novel anti-inflammatoryagents.

炎症JS人体对感染或受伤的自然保护反应，但异常或不受控制 炎症反应弊大于利。适当规定的分解 炎症是多种普通疾病的基础，例如类风湿关节炎，炎症性肠 疾病，多发性硬化症和败血性休克。细胞中细胞促炎基因的表达 免疫系统是炎症发展中最关键的一步。虽然取得了重大进展 已经做出了，促炎基因表达的机制仍未完全了解。长期 该提案的术语目标是了解microRNA的调节和功能 （miRNA），新鉴定的一组短的非编码单链RNA，在pro的表达中 炎症基因。它是促炎性基因，例如肿瘤坏死因子，白介素-1，干旱 环氧合酶2以多种水平的基因表达控制，其中最重要的是 在当时的mrnastsible的调节中。这些促炎性基因的快速mrnadegradation供应 作为控制促炎分子水平的机制。位于 这些短暂的mRNA的未翻译区域决定了它们的退化。我们的研究表明 DICER和ARGONATE（AGO/EIF2C）家庭成员，涉及microRNA（miRNA）处理的组件 和功能是包含ARES（are-mRNA）的mRNA快速衰减所必需的。此外，我们 发现miR16，一种人类mirnawith，一种序列的序列，是序列的 需要mrnaturnover。静息细胞中miR16在are-mRNA衰变中的需求表明 MiR16的生理“家政”功能，在该功能中可以防止高基础促炎的基础水平 基因表达。该建议概述了对miRNA调节的细胞因子基因机制的研究 表达，重点是炎症刺激如何通过阻塞来诱导are-mRNA的稳定 miRNA介导的mRNA降解。在本研究计划中，我们还将评估 MiR16通过全基因组识别和分类miR16靶向基因。为了实现我们的目标，我们将 利用遗传，生化和分子生物学方法的结合。提出的工作 该应用将有助于更好地了解促炎基因表达。理解 miRNA在促炎基因的mRNA稳定性中的功能应为 开发新型的抗炎剂。