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.
Multiple Sclerosis (MS) affects millions and is a debilitating disease with no cure and only modestly effective treatments. This proposal aims to determine the mechanism by which naturally-occurring, plant- derived resveratrol protects from an experimental model of MS, with the long term goal of defining novel therapeutic targets for the treatment of inflammatory and autoimmune diseases.
