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

项目总结 本研究的目的是了解一种名为Bambi-PS1的假基因衍生的长非编码RNA是如何 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方面发挥关键作用。多基因 然而，这些免疫反应的产物，如肿瘤坏死因子，对健康组织也是有毒的。因此， 多个调控电路精确控制这些炎症基因的表达，以维持微妙的 在控制感染/伤害和破坏健康组织之间取得平衡。关键的是，这些设备的故障 调节性事件可导致许多急慢性疾病，如败血症和自身免疫性疾病。 (例如，类风湿性关节炎)等。因此，表征巨噬细胞介导的调节程序 炎症反应将揭示基因表达的基本机制，并提供对 许多免疫紊乱的发病机制。最近的研究揭示了一种新的调节层 由长的非编码RNA介导的炎症反应，它长于200个核苷酸，不 具有功能性蛋白质编码能力。这些RNA可以通过不同的机制调节基因的表达。 我们鉴定了一种真正的lncRNA，Bambi-PS1，它在激活的 炎症反应中的巨噬细胞。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 破译Bambi-PS1介导的巨噬细胞基因表达调控的分子机制。 这一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，但也可能导致先天免疫疾病的新治疗靶点， 比如败血症。

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.