MicroRNA regulation of EAE by resveratrol

描述(申请人提供)：多发性硬化症(MS)是一种神经退行性疾病，导致中枢神经系统神经元周围保护性髓鞘的自身免疫破坏，本质上是虚弱的；然而，患者的预期寿命与普通人群相似，导致巨大的经济负担。多发性硬化症目前还没有治愈方法，目前可用的治疗方法是免疫抑制，患者往往没有反应或产生耐受性，经常转向补充和替代药物(CAM)以缓解症状。因此，开发更好的多发性硬化症诊断工具和治疗方法的必要性显而易见。虽然MS的病因尚不清楚，但细胞介导的免疫机制中的遗传变化已被发现。CD4+T辅助细胞是参与MS的主要免疫细胞，可分化为支持(Th1，Th17)和抗(Th2，Treg)炎症亚型。调节T细胞可塑性的具体方式仍有待确定；然而，microRNAs(MiRNAs)的作用正在显现。因此，这一建议旨在了解调节T细胞分化和功能的直接表观遗传机制，并揭示可操纵以驱动促炎或抗炎T细胞分化的新靶点。白藜芦醇(Res)是一种天然的、植物衍生的化合物，对病原体具有重要的防御作用，对人类健康有许多有益的影响。在MS的实验性自身免疫性脑脊髓炎(EAE)实验模型中，Res发挥神经保护作用并负向调节促炎免疫细胞功能，这一点对这一提议至关重要。在目前的研究中，我们将检验这一中心假设，即自然发生的RES治疗通过miRNA介导的T细胞功能调节和/或抑制前(Th1/Th17)和诱导抗炎(Th2/Treg)T细胞表型来预防神经炎症。在目标1中，我们将通过测试miR-128通过下调磷酸二酯酶10A(PDE10A)来调节T细胞表型和功能的特定假设，来确定miRNA-128在调节脑源性T细胞分化和功能中的作用。为了实现这一点，我们将确定PDE10A作为miR-128的功能靶点，评估miR-128/PDE10A轴在T细胞分化和功能中的作用，并评估miR-128/PDE10A调控对脑源性T细胞表型和功能的影响以及随后的EAE发病机制。在目标2中，我们将通过检验miR-128/PDE10A轴的激活在EAE的选择性保护中的作用这一特定假设，来证明miR-128/PDE10A在RES介导的EAE保护中的作用。为此，我们将评估miR-128/PDE10A调控对RES介导的T细胞表型和功能的影响，并确定miR-128/PDE10A轴的改变如何影响RES诱导的EAE保护作用。本研究探讨了植物来源的Res的作用机制，阐述了miRNA在调节T细胞介导的炎症中的作用，并将为Res如何用于治疗自身免疫性和炎症性疾病提供洞察力。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS), a neurodegenerative disease caused autoimmune destruction of the protective myelin sheaths surrounding neurons in the central nervous system, is debilitating in nature; however, life expectancy of patients is similar o that of the general population resulting in tremendous economic burden. There is no cure for MS and currently available treatments are immunosuppressive and patients are often non-responsive or develop tolerance and frequently turn to complementary and alternative medicine (CAM) for relief. Therefore, the need to develop better diagnostic tools and treatments for MS is immediately obvious. While the etiology of MS remains unclear, genetic alterations in cell-mediated immune mechanisms have been identified. CD4+ T helper cells are the principal immune cell involved in MS and can differentiate into pro- (Th1, Th17) and anti- (Th2, Treg) inflammatory subtypes. The specific ways in which T cell plasticity is regulated remain to be defined; however, there is an emerging role for microRNAs (miRNAs). This proposal is therefore geared towards understanding the direct, epigenetic mechanisms regulating T cell differentiation and function and unveiling novel targets which can be manipulated to drive pro- or anti-inflammatory T cell differentiation. Resveratrol (RES) is a naturally-occurring, plant-derived compound important in defense against pathogens and has numerous beneficial effects on human health. Of central importance to this proposal, RES exerts neuroprotective effects and negatively regulates pro-inflammatory immune cell function in an experimental model of MS, Experimental Autoimmune Encephalomyelitis (EAE). In the current study, we will test the central hypothesis that treatment with naturally-occurring RES prevents neuroinflammation via miRNA-mediated modulation of T cell function and/or suppression of pro- (Th1/Th17) and induction of anti-inflammatory (Th2/Treg) T cell phenotype. In aim 1, we will determine a role for miRNA-128 in regulation of encephalitogenic T cell differentiation and function by testing the specific hypothesis that miR-128 regulates T cell phenotype and function via down-regulation of phosphodiesterase 10A (PDE10A). To achieve this we will identify PDE10A as a functional target of miR-128, asses the role of the miR-128/PDE10A axis in T cell differentiation and function and evaluate the effect of miR-128/PDE10A modulation on encephalitogenic T cell phenotype and function and subsequent pathogenesis of EAE. In aim 2, we will demonstrate a role for miR-128/PDE10A in RES-mediated protection from EAE by testing the specific hypothesis that activation of the miR-128/PDE10A axis plays a role in RES-conferred protection against EAE. To this end, this we will evaluate the effect of miR- 128/PDE10A modulation on RES-mediated T cell phenotype and function and determine how alteration of the miR-128/PDE10A axis affects RES-induced protection from EAE. This study investigates the mechanism of action of plant-derived RES and addresses the role of miRNA in the regulation of T cell-mediated inflammation and will provide insight into how RES may be used to treat autoimmune and inflammatory diseases.