miRNA Regulation of Dendritic Cell Function

*免疫系统具有独特的能力来检测和应对广泛的有害威胁，包括细菌、病毒、寄生虫和癌症。然而，要使免疫反应有效地适应威胁的类型。树突状细胞(DC)是先天细胞，是对任何感染、损伤或外来颗粒的第一反应细胞，在指导免疫反应的类型中起着决定性的作用。这在一定程度上是因为它们能够对不同的刺激做出不同的激活。基因表达的快速和精确变化是DC激活的基础。我的研究项目是研究microRNAs(MiRNAs)调节DC功能的机制。MiRNAs是细胞程序的强大调节者，因为它们能够同时调节多个基因。我们已经发现microRNA-9(miR-9)促进DC的激活及其刺激T细胞反应的能力。在缺少miR-9的情况下，DC不能被激活，也不能刺激T细胞反应。对miR-9假定靶点的通路分析(MsigDB)显示，miR-9假定靶点富含“负调节因子”。本研究的目的是研究miR-9调节DC功能的机制。我们假设miR-9通过靶向DC激活所必需的几个细胞通路的负调控来促进DC激活。在此，我们建议研究miR-9如何通过靶向转录、翻译、mRNA稳定性和抑制性细胞因子的信号负调控来调节DC的功能。该研究计划的长期目标是研究在我们的RNAseq数据集中识别的miRNAs，以及除了miR-9之外，最终它们和它们的靶向通路如何协作调节DC功能。*目的：*1.确定miR-9调控DC转录的机制。*2.确定miR-9对DC翻译和mRNA稳定性的调节。*3.确定miR-9是否促进3型免疫反应的发展。*4.确定miR-9对不同DC亚群基因表达的直接和间接调控范围。*这项建议继续了我之前由NSERC资助的工作，即剖析miRNAs在调节DC对炎症刺激的早期反应中的作用。我们将研究miR-9调节DC功能的机制。通过对miR-9靶点的研究，我们还将描述调节DC功能的新机制。这些研究将有助于我们全面了解使DC能够启动上下文特异性免疫反应的分子机制。

***The immune system possesses the unique capacity to detect and respond to broad range of harmful threats including bacteria, viruses, parasites and cancer. However, for an immune response to be effective tailored to the type of threat. Dendritic cells (DCs) are innate cells that are among the first responders to any infection, injury or foreign particle and play a decisive role in directing the type of immune response. This in part due to their ability to become differentially activated in response to diverse stimuli . Rapid and precise changes in gene expression underlie DC activation. My research program investigates the mechanisms by which microRNAs (miRNAs) regulate of DC function. miRNAs are powerful regulators of cellular programs by their ability to regulate multiple genes simultaneously. We have found that microRNA-9 (miR-9) promotes DC activation and their ability to stimulate T cell responses. In the absence of miR-9, DCs fail to become activated and cannot stimulate T cell responses. Pathway analyses (MsigDB) of the putative targets of miR-9 (Targetscan) revealed that miR-9 putative targets are enriched in “negative regulators”.******The goal of this proposal is to investigate the mechanisms by which miR-9 regulates DC function. We hypothesize that miR-9 facilitates DC activation by targeting negative regulators of several cellular pathways essential for DC activation. Herein we propose to study how miR-9 regulates DC function by targeting negative regulators of transcription, translation, mRNA stability and signaling of repressive cytokines. The long-term goals of this research program are to study miRNAs identified in our RNAseq dataset, in addition to miR-9, and ultimately how they and their targeted pathways cooperate to regulate DC function. ******Objectives:***1. To determine the mechanism by which miR-9 regulates transcription in DCs. ***2. To determine the regulation of translation and mRNA stability by miR-9 in DCs. ***3. To determine whether miR-9 promotes development of Type 3 immune responses. ***4. To determine the scope of direct and indirect regulation of gene expression by miR-9 in different DC subsets. ******This proposal continues my work previously funded by NSERC to dissect the role of miRNAs in regulating early DC responses to inflammatory stimuli. We will investigate the mechanisms by which miR-9 regulates DC function. Through studying miR-9 targets we will also describe novel mechanisms that regulate DC function. These studies will contribute to our comprehensive understanding of the molecular mechanisms that enable DCs to mount context-specific immune responses.