miRNA Regulation of Dendritic Cell Function

树突状细胞功能的 miRNA 调节

• 批准号: RGPIN-2018-06257
• 负责人: Krawczyk, Connie
• 金额: $ 2.62万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=655983
• 关键词: miRNA; Regulation; Dendritic; Cell; Function

***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.

***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针对威胁类型进行调整。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者之一，在指导免疫反应的类型中起决定性作用。这在一定程度上是由于它们对不同刺激的反应能力不同。快速和精确的基因表达变化是DC激活的基础。我的研究项目是研究microRNAs （miRNAs）调控DC功能的机制。mirna通过同时调节多个基因的能力，是细胞程序的强大调节剂。我们发现microRNA-9 （miR-9）促进DC激活及其刺激T细胞反应的能力。在缺乏miR-9的情况下，dc不能被激活，不能刺激T细胞反应。miR-9的推定靶点（Targetscan）的通路分析（MsigDB）显示miR-9的推定靶点富含“负调节因子”。******本提案的目的是研究miR-9调节DC功能的机制。我们假设miR-9通过靶向DC激活所必需的几种细胞通路的负调节因子来促进DC激活。在此，我们提出研究miR-9如何通过靶向抑制细胞因子的转录、翻译、mRNA稳定性和信号转导的负调节因子来调节DC功能。该研究计划的长期目标是研究我们的RNAseq数据集中鉴定的mirna，以及miR-9，并最终研究它们及其靶向通路如何协同调节DC功能。* * * * * *的目标:* * * 1。确定miR-9调控dc中转录的机制。* * * 2。探讨miR-9在dc中对翻译和mRNA稳定性的调控作用。* * * 3。确定miR-9是否促进3型免疫反应的发展。* * * 4。确定miR-9在不同DC亚群中直接和间接调控基因表达的范围。******该提案继续了我之前由NSERC资助的工作，以解剖mirna在调节早期DC对炎症刺激的反应中的作用。我们将研究miR-9调控DC功能的机制。通过研究miR-9靶点，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产生上下文特异性免疫反应的分子机制。