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

项目概要 本研究的目的是了解假基因衍生的长非编码 RNA（名为 Bambi-ps1）如何 调节巨噬细胞介导的炎症反应。巨噬细胞是一种重要的先天免疫细胞， 在检测危险信号和产生适当的炎症反应方面发挥着关键作用。许多基因 然而，这些免疫反应的产物（例如肿瘤坏死因子）对健康组织也有毒。因此， 多个调节回路精确控制这些炎症基因的表达，以维持微妙的 控制感染/损伤和损害健康组织之间的平衡。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，类风湿性关节炎）等。因此，描述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见解 许多免疫学疾病的发病机制。最近的研究揭示了一种新的监管层 由长非编码RNA介导的炎症反应，其长度超过200个核苷酸，并且不 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。 我们鉴定了一个真正的 lncRNA，Bambi-ps1，它在激活的 炎症反应期间的巨噬细胞。此外，我们的初步数据表明 Bambi-ps1 是 体内和体外适当的炎症反应所必需的。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节的分子机制。 这些结果不仅揭示了巨噬细胞介导的基因表达的新调控机制 炎症反应，还可能为先天性免疫疾病带来新的治疗靶点， 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.