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Function of microRNA in pro-inflammatory gene expression

microRNA在促炎基因表达中的功能

基本信息

批准号：
8008824
负责人：
PETER S TOBIAS
金额：
$ 45.55万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8008824
关键词：
3&apos 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 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 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

项目摘要

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.

炎症是机体对感染或损伤的自然保护性反应，但不正常或不受控制炎症反应可能弊大于利。适当监管的细分炎症是一系列常见疾病的基础，如类风湿性关节炎、肠炎、多发性硬化症和感染性休克。促炎基因的表达由细胞在免疫系统是炎症发展的最关键步骤。虽然取得了重大进展，尽管已经取得了一些进展，但促炎基因表达的机制仍不完全清楚。很长的- 本提案的长期目标是了解microRNA的调控和功能一组新发现的短的非编码单链RNA（miRNA），在前- 炎症基因众所周知，促炎基因如肿瘤坏死因子、白细胞介素-1和环氧合酶2在多个基因表达水平上受到控制，其中最重要的一个是在调节then-mRNA稳定性方面。这些促炎基因的快速mRNA降解作为控制促炎分子水平的机制。富Au元素（战神）位于这些短寿命mRNA的3'非翻译区决定了它们的降解。我们最近的研究显示， Dicer和Argonaute（Ago/eif 2C）家族成员，参与microRNA（miRNA）加工的组分和功能，是含有战神的mRNA（ARE-mRNA）快速衰变所必需的。而且我们发现miR 16，一种人类miRNAs，其序列与ARE序列部分互补，是ARE-mRNA周转所必需的。miR 16在静息细胞中ARE-mRNA衰变中的需求表明， miR 16的生理“管家”功能，其中它阻止高基础水平的促炎性细胞因子，基因表达。本研究拟对miRNA调控细胞因子基因表达的机制进行研究表达，重点是炎症刺激如何通过阻断ARE-mRNA的表达来诱导ARE-mRNA的稳定。 miRNA介导的mRNA降解。在本研究计划中，我们还将评估通过对miR 16靶向基因的全基因组鉴定和分类来鉴定miR 16。为了实现我们的目标，我们将利用遗传、生物化学和分子生物学方法的组合。建议的工作该应用将有助于更好地理解促炎基因表达。理解 miRNA在促炎基因mRNA稳定性中的功能应该提供新的途径，开发新的抗炎剂。