Role and Regualtion of miRNA223 in EAE

有迅速积累的证据表明microRNA（miRs）在 调节免疫细胞发育/功能。最近我们做了一个重要的 观察到miR 223不仅在患病的中枢神经系统中增加， (CNS)而且在EAE小鼠的外周免疫区室中， 多发性硬化症（MS）。值得注意的是，EAE脊髓中miR 223表达的增加与EAE脊髓中miR 223表达的增加有关。 被抗免疫剂1，25（OH）2D 3阻断。此外，MS患者的miR 223 血细胞升高这些发现指出miR 223在CNS中的致病作用。 自身免疫性炎症现在我们已经获得了令人信服的证据来支持这一点 前提;即在造血干细胞中miR 223的全面或条件性废除， 干细胞衍生的免疫细胞导致对EAE的显著抗性。这些 突破性进展确立miR 223为调节CNS自身免疫的新型miR 炎症我们的目标是进一步评估miR 223在EAE发病机制中的作用 并确定miR 223的作用机制。我们首先要核实一下， 自身抗原诱导的miR 223表达是EAE的原因而不是结果。我们 将通过研究miR 223诱导开始的时间顺序来解决这个问题 和脱髓鞘，然后研究miR 223功能性阻断是否会减少 脱髓鞘然后，我们将确定miR 223促进细胞凋亡的细胞机制。 EAE。具体来说，我们将检验miR 223促进轴突生长的假设。 脱髓鞘通过增强致病性Th 17和M1巨噬细胞极化， 条件性敲除和细胞特异性拯救。最后，我们将确定和功能 表征miR 223的下游介质，即miR 223靶基因， EAE。我们已经确定了一系列潜在的miR 223靶点， 筛选策略。我们将重点关注两个潜在的神经保护基因，单核细胞 增强子因子（Mef 2c），一种已知的miR 223靶点，和脂多糖应答性 beige-like锚基因（Lrba），一个潜在的新靶点。我们的工作很可能会发现 中枢神经系统自身免疫发展的新机制。在临床方面， 这项工作的相关性，miR 223的作用和作用机制的鉴定 在EAE中的应用可能会导致基于miR 223的治疗方法的发展， MS，发生在平民和退伍军人群体中。

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.