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

• 批准号: 10406376
• 负责人: Wenqian Hu
• 金额: $ 19.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-17 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406376
• 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

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 本研究的目的是了解一个假基因衍生的长非编码RNA 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， 在检测危险信号和建立适当的炎症反应中起着关键作用。许多基因 然而，来自这些免疫应答的产物，例如TNF，对健康组织也是有毒的。因此，在本发明中， 多个调节回路精确地控制这些炎症基因的表达， 在管理感染/损伤和损害健康组织之间保持平衡。关键是，这些故障 调节事件可导致许多急性和慢性疾病，如败血症和自身免疫性疾病 (e.g.,因此，表征巨噬细胞介导的调节程序， 炎症反应既揭示了基因表达的基本机制， 许多免疫紊乱的发病机制。最近的研究揭示了一个新的调节层， 由长的非编码RNA介导的炎症反应，其长于200个核苷酸， 具有功能性蛋白质编码能力。这些RNA可以通过多种机制调节基因表达。 我们鉴定了一种真正的lncRNA，Bambi-ps1，它在活化的细胞中大量特异性表达。 巨噬细胞在炎症反应。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 破译Bambi-ps1介导的巨噬细胞基因表达调控的分子机制。 这些结果不仅将揭示巨噬细胞介导的基因表达的新调控机制， 炎症反应，而且还可能为先天免疫疾病带来新的治疗靶点， 例如败血症。