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，引起中枢神经系统神经元周围保护性髓鞘的自身免疫破坏，本质上使人衰弱；然而，患者的预期寿命与一般人群相似，造成了巨大的经济负担。目前还没有治愈多发性硬化症的方法，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，经常求助于补充和替代药物（CAM）来缓解。因此，开发更好的诊断工具和治疗多发性硬化症的需要是显而易见的。虽然MS的病因尚不清楚，但已经确定了细胞介导的免疫机制的遗传改变。CD4+ T辅助细胞是参与MS的主要免疫细胞，可分化为亲（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）有一个新兴的作用。因此，该建议旨在了解调节T细胞分化和功能的直接表观遗传机制，并揭示可以操纵驱动促或抗炎T细胞分化的新靶点。白藜芦醇（Resveratrol， RES）是一种天然存在的植物衍生化合物，对防御病原体很重要，对人体健康有许多有益的影响。对这一提议至关重要的是，RES在MS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性调节促炎免疫细胞功能。在目前的研究中，我们将验证中心假设，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。在目的1中，我们将通过验证miR-128通过下调磷酸二酯酶10A （PDE10A）调节T细胞表型和功能的特定假设，确定miRNA-128在调节脑源性T细胞分化和功能中的作用。为了实现这一目标，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调节对脑源性T细胞表型和功能以及EAE后续发病机制的影响。在目的2中，我们将通过验证miR-128/PDE10A轴的激活在res赋予的EAE保护中起作用的特定假设，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调制对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。本研究探讨了植物源性RES的作用机制，并解决了miRNA在T细胞介导的炎症调节中的作用，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.