Role and Regualtion of miRNA223 in EAE

越来越多的证据表明，microRNAs(MiRs)在 调节免疫细胞的发育/功能。最近我们做了一个重要的 观察到miR223不仅在病变的中枢神经系统中增加 (CNS)，而且在EAE小鼠的外周免疫隔膜中，也是一种 多发性硬化(MS)。值得注意的是，miR223在EAE脊髓中的表达增加 被抗免疫剂1，25(OH)2D3阻断。此外，多发性硬化症患者体内的miR223 血细胞升高。这些发现表明miR223在中枢神经系统中起致病作用。 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，在造血系统中全局或有条件地取消miR223 干细胞来源的免疫细胞对EAE具有显著的抵抗力。这些 突破性进展使miR223成为调节中枢神经系统自身免疫的新miR 发炎。我们的目标是进一步评价miR223‘S在EAE发病机制中的作用 并对miR223‘S作用机制进行了初步探讨。我们将首先核实 自身抗原诱导的miR223表达是EAE的原因而不是结果。我们 我将通过研究miR223诱导开始的时间序列来解决这个问题 和脱髓鞘，然后调查miR223功能阻断是否会减少 脱髓鞘。然后我们将确定miR223促进的细胞机制 EAE。具体地说，我们将测试miR223促进轴突的假设 增强致病Th17和M1巨噬细胞极化的脱髓鞘作用 有条件的基因敲除和细胞特异性的拯救。最后，我们将确定并在功能上 鉴定miR223的下游介体，即miR223的靶基因 EAE。我们已经确定了一系列潜在的miR223目标，使用精心设计的 筛选策略。我们将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，与内毒素反应 米色样锚基因(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，确定miR223的作用和作用机制 可能导致基于miR223的治疗方法的开发 多发性硬化症，在平民和退伍军人中都会发生。

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.