Role and Regualtion of miRNA223 in EAE

miRNA223在EAE中的作用和调控

• 批准号: 8974335
• 负责人: Xuezhong Qin
• 金额: --
• 依托单位: VA LOMA LINDA HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974335
• 关键词: 3' Untranslated Regions; Address; Age; Animal Model; Autoantigens; Autoimmune Process; Autoimmunity; Binding; Binding Sites; Biological Assay; Blood Cells; Bone Marrow; Brain Diseases; Cell Lineage; Cells; Chimera organism; Data; Defect; Demyelinations; Development; Enhancers; Experimental Autoimmune Encephalomyelitis; Gene Silencing; Gene Targeting; Genes; Goals; Gulf War; Health; Hematopoietic stem cells; Immune; Immune response; Incidence; Inflammation; Knock-out; Knockout Mice; Lead; Lentivirus Vector; Lipopolysaccharides; Luciferases; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Military Personnel; Mission; Molecular; Multiple Sclerosis; Mus; Muscle Cells; Nerve; Pathogenesis; Peripheral; Population; Porifera; Prevalence; Rage; Reporter; Research Personnel; Resistance; Role; Spinal Cord; System; T-Lymphocyte; Testing; Veterans; Woman; Work; base; clinically relevant; design; macrophage; man; monocyte; mouse model; multiple sclerosis patient; multiple sclerosis treatment; novel; novel therapeutics; overexpression; prevent; screening; small hairpin RNA; trend

DESCRIPTION (provided by applicant): There is rapidly accumulating evidence for a pivotal role of microRNAs (miRs) in regulating immune cell development/function. Recently we made an important observation that miR223 was increased not only in the diseased central nerve system (CNS) but also in the peripheral immune compartments of EAE mice, an animal model of multiple sclerosis (MS). Notably, increased miR223 expression in EAE spinal cord was blocked by an anti-immune agent 1,25(OH)2D3. Moreover, miR223 in the MS patient's blood cells was elevated. These findings point to a pathogenic role of miR223 in CNS autoimmune inflammation. Now we have obtained compelling evidence to support this premise; namely, abrogation of miR223 either globally or conditionally in hematopoietic stem cell-derived immune cells resulted in a remarkable resistance to EAE. These breakthroughs establish miR223 as a novel miR in regulating CNS autoimmune inflammation. Our goal is to further evaluate miR223's function in pathogenesis of EAE and identify the mechanisms of the miR223's action. We will first verify that autoantigen-elicited miR223 expression is the cause rather than the result of EAE. We will address this issue by studying the temporal sequence in onset of miR223 induction and demyelination, followed by investigating if miR223 functional blockade will reduce demyelination. We will then identify the cellular mechanism by which miR223 promotes EAE. Specifically we will test the hypothesis that miR223 promotes axonal demyelination by enhancing pathogenic Th17 and M1 macrophage polarization using conditional knockout and cell-specific rescue. Finally, we will identify and functionally characterize the downstream mediators of miR223, namely the miR223 target genes, in EAE. We have identified a list of potential miR223 targets using carefully designed screening strategies. We will focus on two potentially neuroprotective genes, monocyte enhancer factor (Mef2c), a known miR223 target, and the lipopolysaccharide responsive beige-like anchor gene (Lrba), a potentially novel target. Our work will likely uncover new mechanisms by which autoimmunity develop in CNS. In terms of the clinical relevance of this work, identification of the role and mechanism of the action of miR223 in EAE could potentially lead to development of miR223-based therapy for treatment of MS, which occurs in both civilian and military-veteran populations.

描述（由申请人提供）： 越来越多的证据表明 microRNA (miR) 在调节免疫细胞发育/功能中发挥着关键作用。最近我们做了一个重要的观察，即 miR223 不仅在患病的中枢神经系统（CNS）中增加，而且在 EAE 小鼠（多发性硬化症（MS）动物模型）的外周免疫室中也增加。值得注意的是，EAE 脊髓中 miR223 表达的增加被抗免疫剂 1,25(OH)2D3 阻断。此外，MS 患者血细胞中的 miR223 升高。这些发现表明 miR223 在 CNS 自身免疫炎症中的致病作用。现在我们已经获得了令人信服的证据来支持这个前提；也就是说，在造血干细胞衍生的免疫细胞中全局或有条件地消除 miR223 会导致对 EAE 的显着抵抗。这些突破确立了 miR223 作为调节中枢神经系统自身免疫炎症的新型 miR。我们的目标是进一步评估 miR223 在 EAE 发病机制中的功能并确定 miR223 的作用机制。我们将首先验证自身抗原引发的 miR223 表达是 EAE 的原因而不是结果。我们将通过研究 miR223 诱导和脱髓鞘发生的时间序列来解决这个问题，然后研究 miR223 功能阻断是否会减少脱髓鞘。然后我们将确定 miR223 促进 EAE 的细胞机制。具体来说，我们将测试以下假设：miR223 通过使用条件敲除和细胞特异性拯救增强致病性 Th17 和 M1 巨噬细胞极化来促进轴突脱髓鞘。最后，我们将鉴定并功能表征 EAE 中 miR223 的下游介质，即 miR223 靶基因。我们使用精心设计的筛选策略确定了一系列潜在的 miR223 靶标。我们将重点关注两个潜在的神经保护基因，单核细胞增强因子 (Mef2c)（一个已知的 miR223 靶标）和脂多糖反应性米色样锚定基因 (Lrba)（一个潜在的新靶标）。我们的工作可能会揭示中枢神经系统自身免疫发展的新机制。就这项工作的临床相关性而言，确定 miR223 在 EAE 中的作用和作用机制可能会导致开发基于 miR223 的治疗 MS 的疗法，这种疗法发生在平民和退伍军人群体中。