Dissecting how inflammation-induced tenascin-C regulates the master mediator of inflammation miR-155

剖析炎症诱导的腱蛋白-C 如何调节炎症的主要介质 miR-155

• 批准号: 2271368
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2271368
• 关键词: Dissecting; how; inflammation; induced; tenascin

During infection conserved microbial components are detected by innate immune cells such as macrophages which possess pattern recognition receptors, including Toll-like receptors (TLRs). Once activated, TLRs initiate inflammatory responses that culminate with the production of inflammatory mediators such as cytokines that subsequently prime specific adaptive immune responses. Dysregulation of this process can lead to inflammatory and autoimmune diseases such as sepsis, rheumatoid arthritis and systemic lupus erythematosus. Therefore TLR signalling must be tightly regulated. MicroRNAs, small noncoding RNAs, are important regulators of gene expression that control TLR signalling and cytokine synthesis. Several microRNAs are induced upon infection by TLR activation in macrophages and these microRNAs function by targeting the 3' untranslated region (UTR) of mRNAs encoding components of the TLR signalling system and the downstream cytokines. We found that the extracellular matrix glycoprotein tenascin-C (TN-C) regulates the production of the pro-inflammatory cytokine TNF-a in macrophages activated by the bacterial component lipopolysaccharide (LPS). TN-C does this by regulating the expression of the microRNA miR-155. However, how TN-C exactly regulates miR-155 biogenesis is unknown. The overall hypothesis of the project builds on our preliminary data which suggests that TN-C regulates miR-155 biogenesis at the post-transcriptional level. Specifically, in the presence of TN-C enzymatic cleavage of the miR-155 primary transcript by Drosha in the nucleus is significantly more efficient. The aims are: 1. Determine the molecular mechanism by which TN-C regulates miR-155 processing in the nucleus. 2. Establish whether the identified regulatory mechanism is specific to miR-155 or applies to other miRNAs. The project will benefit from the expertise of the Piccinini group (molecular immunology, microRNAs and cell biology) and Jopling group (microRNA regulation).

在感染过程中，具有模式识别受体的天然免疫细胞(如巨噬细胞)检测到保守的微生物成分，包括Toll样受体(TLRs)。一旦被激活，TLRs就会启动炎症反应，最终产生炎症介质，如细胞因子，然后启动特定的适应性免疫反应。这一过程的失调可能导致炎症和自身免疫性疾病，如脓毒症、类风湿性关节炎和系统性红斑狼疮。因此，TLR信令必须受到严格监管。MicroRNAs是一种非编码的小RNA，是控制TLR信号和细胞因子合成的基因表达的重要调节者。巨噬细胞中TLR的激活可诱导几种microRNAs的表达，这些microRNAs通过靶向编码TLR信号系统各组成部分的mRNAs的3‘非翻译区和下游的细胞因子发挥作用。我们发现，细胞外基质糖蛋白TN-C(TN-C)调节细菌成分脂多糖(LPS)激活的巨噬细胞产生促炎细胞因子TNF-a。TN-C通过调节microRNA miR-155的表达来做到这一点。然而，TN-C如何准确调控miR-155的生物发生尚不清楚。该项目的总体假设建立在我们的初步数据基础上，该数据表明TN-C在转录后水平上调节miR-155的生物发生。具体地说，在TN-C的存在下，DROSHA在细胞核中对miR-155初级转录本的切割效率明显更高。其目的是：1.确定TN-C调控miR-155在核内加工的分子机制。2.确定所确定的调控机制是针对miR-155还是适用于其他miRNAs。该项目将受益于Piccinini小组(分子免疫学、microRNAs和细胞生物学)和Joving小组(microRNA调节)的专业知识。