MicroRNA regulation of EAE by resveratrol

描述（由申请人提供）：多发性硬化症（MS）是一种神经退行性疾病，由中枢神经系统中神经元周围的保护性髓鞘的自身免疫性破坏引起，本质上是使人衰弱的;然而，患者的预期寿命与一般人群相似，导致巨大的经济负担。MS无法治愈，目前可用的治疗方法是免疫抑制，患者通常无反应或产生耐受性，并经常转向补充和替代医学（CAM）以缓解。因此，开发更好的MS诊断工具和治疗方法的需求是显而易见的。虽然MS的病因尚不清楚，但已确定细胞介导的免疫机制中的遗传改变。CD 4 + T辅助细胞是参与MS的主要免疫细胞，并且可以分化成促炎性（Th 1，Th 17）和抗炎性（Th 2，Treg）亚型。调节T细胞可塑性的具体方式仍有待确定;然而，microRNA（miRNAs）正在发挥作用。因此，该提案旨在了解调节T细胞分化和功能的直接表观遗传机制，并揭示可被操纵以驱动促炎或抗炎T细胞分化的新靶点。白藜芦醇（RES）是一种天然存在的植物源化合物，在防御病原体方面很重要，对人类健康有许多有益的影响。对于这一提议至关重要的是，RES在MS的实验模型（实验性自身免疫性脑脊髓炎（EAE））中发挥神经保护作用并负调节促炎免疫细胞功能。在目前的研究中，我们将测试的中心假设，即治疗与自然发生的RES通过miRNA介导的调节T细胞功能和/或抑制前（Th 1/Th 17）和诱导抗炎（Th 2/Treg）T细胞表型预防神经炎症。在目标1中，我们将通过检验miR-128通过下调磷酸二酯酶10A（PDE 10A）来调节T细胞表型和功能的特定假设，来确定miRNA-128在致脑炎性T细胞分化和功能调节中的作用。为了实现这一点，我们将鉴定PDE 10A作为miR-128的功能靶标，评估miR-128/PDE 10A轴在T细胞分化和功能中的作用，并评估miR-128/PDE 10A调节对致脑炎性T细胞表型和功能以及随后的EAE发病机制的影响。在目标2中，我们将通过检验miR-128/PDE 10A轴的激活在RES赋予的针对EAE的保护中起作用的特定假设来证明miR-128/PDE 10A在RES介导的针对EAE的保护中的作用。为此，我们将评估miR- 128/PDE 10A调节对RES介导的T细胞表型和功能的影响，并确定miR-128/PDE 10A轴的改变如何影响RES诱导的EAE保护。这项研究调查了植物来源的RES的作用机制，并解决了miRNA在调节T细胞介导的炎症中的作用，并将提供RES如何用于治疗自身免疫性和炎症性疾病的见解。

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.