Mechanistic studies of a long noncoding RNA in macrophage-mediated inflammatory responses

长链非编码RNA在巨噬细胞介导的炎症反应中的机制研究

基本信息

批准号：
10288845
负责人：
Wenqian Hu
金额：
$ 23.85万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-17 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288845
关键词：
Acute Disease Address Amino Acids Antisense RNA Apoptosis Area Autoimmune Diseases Binding Biological Biological Process Bone Marrow Cells Chromatin Chronic Disease Code Collaborations Computational algorithm Data Discrimination Equilibrium Erythrocytes Event Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Hypersensitivity Immune Immune System Diseases Immune response In Vitro Inflammatory Inflammatory Response Injury Innate Immune Response Interleukin-6 Knockout Mice Knowledge Lead Lipopolysaccharides Mediating Messenger RNA Methods Molecular Names Nuclear Nucleotides Open Reading Frames Pathogenesis Play Proteins Pseudogenes RNA Regulation Rheumatoid Arthritis Ribosomes Role Sepsis Signal Transduction TNF gene Testing Tissues Transcript Untranslated RNA Wild Type Mouse cytokine differential expression erythroid differentiation gene product in vivo infection management insight loss of function macrophage mouse model new therapeutic target novel programs ribosome profiling transcriptomics

Acute Disease Address Amino Acids Antisense RNA Apoptosis Area Autoimmune Diseases Binding Biological Biological Process Bone Marrow Cells Chromatin Chronic Disease Code Collaborations Computational algorithm Data Discrimination Equilibrium Erythrocytes Event Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Hypersensitivity Immune Immune System Diseases Immune response In Vitro Inflammatory Inflammatory Response Injury Innate Immune Response Interleukin-6 Knockout Mice Knowledge Lead Lipopolysaccharides Mediating Messenger RNA Methods Molecular Names Nuclear Nucleotides Open Reading Frames Pathogenesis Play Proteins Pseudogenes RNA Regulation Rheumatoid Arthritis Ribosomes Role Sepsis Signal Transduction TNF gene Testing Tissues Transcript Untranslated RNA Wild Type Mouse cytokine differential expression erythroid differentiation gene product in vivo infection management insight loss of function macrophage mouse model new therapeutic target novel programs ribosome profiling transcriptomics

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项目摘要

PROJECT SUMMARY The goal of this study is to understand how a pseudogene-derived long noncoding RNA named Bambi-ps1 regulates macrophage-mediated inflammatory responses. Macrophages, a vital type of innate immune cell, play critical roles in detecting danger signals and mounting proper inflammatory responses. Many gene products from these immune responses, such as TNF, however, are also toxic to healthy tissues. Thus, multiple regulatory circuits precisely control the expression of these inflammatory genes to maintain a delicate balance between managing infection/injury and damaging healthy tissues. Critically, malfunction of these regulatory events can result in many acute and chronic diseases, such as sepsis and autoimmune disorders (e.g., rheumatoid arthritis), etc. Thus, characterizing regulatory programs in macrophage-mediated inflammatory responses will both reveal fundamental mechanisms of gene expression and provide insights into the pathogenesis of many immunological disorders. Recent studies revealed a novel layer of regulation of inflammatory responses mediated by long noncoding RNAs, which are longer than 200 nucleotides and do not have functional protein-coding capacity. These RNAs can regulate gene expression via diverse mechanisms. We identified a bona fide lncRNA, Bambi-ps1, which is abundantly and specifically expressed in activated macrophages during inflammatory responses. Moreover, our preliminary data indicated that Bambi-ps1 is required for proper inflammatory responses both in vivo and in vitro. In this explorative study, we plan to decipher the molecular mechanisms of Bambi-ps1-mediated regulation of gene expression in macrophages. The results will not only reveal novel regulatory mechanisms of gene expression in macrophage-mediated inflammatory responses but also may potentially result in new therapeutic targets for innate immune disorders, such as sepsis.

项目摘要这项研究的目的是了解伪基因衍生的长期非编码RNA如何名为BAMBI-PS1 调节巨噬细胞介导的炎症反应。巨噬细胞，一种重要的先天免疫细胞，在检测危险信号和安装适当的炎症反应中发挥关键作用。许多基因但是，来自这些免疫反应的产物（例如TNF）也对健康组织有毒。因此，多个调节电路精确地控制着这些炎症基因的表达，以保持微妙在管理感染/受伤和破坏健康组织之间取得平衡。至关重要的是这些故障调节事件可能导致许多急性和慢性疾病，例如败血症和自身免疫性疾病（例如，类风湿关节炎）等。因此，表征巨噬细胞介导的调节程序炎症反应既可以揭示基因表达的基本机制，又提供了洞察力许多免疫疾病的发病机理。最近的研究揭示了对由长的非编码RNA介导的炎症反应，该反应长于200个核苷酸，不超过200个核苷酸具有功能性蛋白质编码能力。这些RNA可以通过各种机制调节基因表达。我们确定了一个真正的lncrna，bambi-ps1，在激活中大量而专门表达炎症反应过程中的巨噬细胞。此外，我们的初步数据表明BAMBI-PS1是在体内和体外都需要适当的炎症反应。在这项探索性研究中，我们计划 BAMBI-PS1介导的巨噬细胞中基因表达的调节的分子机制破译。结果不仅会揭示巨噬细胞介导的基因表达的新调节机制炎症反应，但也可能导致新的治疗靶点，用于先天免疫疾病，例如败血症。