新型BET Bromodomain抑制剂治疗多发性硬化炎症反应的机制研究

Multiple sclerosis is an autoimmune disease whose onset likely involves invasion of inflammatory cells in the central nervous system. Studies show that over-development of T-helper 17 (Th17) cells contributes to inflammatory disorders including multiple sclerosis. Th17 cells development from naïve CD4+ T cells requires transcriptional activation of inflammatory cytokines under the influence of transcriptional regulators of the BET family proteins that function through their bromodomains binding to acetylated-lysine residues in histones and transcription factors. We have recently developed novel small-molecule bromodomain inhibitor named MS402 that can selectively modulate the BET protein function in gene transcriptional activation in Th17 cells. Specially, in our recent study, we show that this new inhibitor can effectively suppress lineage-specific differentiation of Th17 cells from naïve T cells, but not affect cell differentiation of other Th subtypes such as Th2 and Treg. We postulate that this new epigenetic chemical modulator could work as a targeted therapy for multiple sclerosis whose progression has been suggested to involve Th17 cells development. Towards this end, we propose to investigate in vivo efficacy of MS402 in modulating differentiation of Th17 cells during the disease development using the EAE model of multiple sclerosis in mice. Our study will yield important mechanistic insights into gene transcriptional regulation of Th17 cell development in multiple sclerosis, and facilitate the development of a new targeted epigenetic therapy for the treatment of this challenging inflammatory disorder.

多发性硬化是一类由中枢神经系统损伤引起的自身免疫性疾病,与辅助性T细胞Th17的异常分化密切相关。BET蛋白家族是一类特异性识别乙酰化赖氨酸位点的蛋白,Th17细胞的分化过程需要BET蛋白调控的多种炎症因子的分泌。我们基于BET蛋白对于炎症反应的调控作用,合成了一种新型的BET Bromodomain抑制剂MS402。我们的前期实验结果证实,新型的抑制剂MS402能够选择性的抑制Th17细胞的分化 ,但是对Th2和Treg的分化不影响。因此我们推测,新型的抑制剂MS402作为靶向治疗药物,能够对Th17异常分化引起的自身免疫性疾病——多发性硬化中的炎症反应起到治疗作用。我们将通过建立EAE模型,在动物水平检测MS402对多发性硬化的治疗作用。我们的研究将会揭示Th17细胞的分化对多发性硬化发病进程的调控作用，以及这一新的化合物作为多发性硬化治疗药物的理论依据及作用机制。