RARa信号经嘌呤途径调节炎性肠病Th17/Treg免疫反应的研究

Imbalanced Th17/Treg responses contribute to pathogenesis of inflammatory bowel disease (IBD), with dominant Th17 but deficient Treg responses. In previous NSFC-funded project, we have found that RARa signal can modulate Treg/Th17 responses, and attenuate immune reponses of IBD, while the key question about molecular mechanism how RARa signal controls Th17/Treg responses is still to be elucidated. Recently, the function of purine signaling on regulating Th17/Treg responses has been addressed. Our preliminary data show that RAR signal in vitro modulates purine signaling including CD39 and CD73 expressions and extracellular ATP and adenosine products, and Th17/Treg differentiation thereafter, indicating purine signaling as a downstream pathway of RARa signal, and a regulator of Th responses. We hypothesize that RARa signal regualtes Th17/Treg balance and immune responses of IBD through controlling purine signaling. We propose to address the downstream pathway of RARa signal and its function in two specific aims. First, to investigate the effect of RARa signal on purine signaling of CD4+ T cells, and Th17/Treg responses and the molecular mechanisms. Second, to explore the impact of RARa signal on purine signaling and immune responses of animal models of colitis and human IBD. The project will be performed with CD4+ T cells in vitro, experimental models of colitis and human IBD, to discuss the mechanism that RARa signal modulates purine signaling, Th17/Treg function, and aberrant immune responses of IBD and murine colitis. In summary, the proposed project will provide novel information about the mechanisms and molecular targets of RARa-initiated purine signaling, and may offer a promising alternative to our current approaches of managing autoimmune diseases including IBD.

Th17/Treg7反应失衡在IBD发病中发挥重要作用，前一课题发现RARa信号能诱导IBD肠粘膜Treg分化，并抑制Th17反应。然而，RARa信号如何调节Th17/Treg平衡、抑制肠粘膜炎症反应等直接关系其病理机制的分子机制尚亟待研究。本研究以RARa信号通过调节嘌呤通路，调控Th17/Treg分化的前期结果为切入点，进一步体外研究RARa信号对IBD及实验性结肠炎CD4+ T细胞嘌呤途径的调节，及肠粘膜Treg/Th17功能的调节；同时利用小鼠结肠炎模型，探讨体内RARa信号对嘌呤途径、肠道炎症反应的抑制作用及机制。从细胞、动物、人体多方面来探讨Treg/Th17失衡、嘌呤途径在IBD发病中作用，及RARa信号调节嘌呤途径、炎症肠粘膜Treg/Th17平衡、抑制肠道炎症反应的机制，为将来利用RARa信号和嘌呤途径治疗IBD、深入RARa信号和嘌呤途径的药理研发打下理论研究基础

嘌呤途径能调节机体Th细胞免疫反应。课题研究了RARa信号RARα信号能诱导Treg分化，并抑制Th17的分化，同时RARa信号能调节CD39/CD73及嘌呤通路，提示RARa信号可通过调节嘌呤通路调控炎症性肠病（IBD）肠道Th17/Treg分化和功能；研究进一步体外研究RARa信号对IBD及实验性结肠炎CD4+ T细胞嘌呤途径的调节，及肠粘膜Treg/Th17功能的调节；同时利用小鼠结肠炎模型，探讨体内RARa信号对嘌呤途径、肠道炎症反应的抑制作用及机制。研究从细胞、动物、人体多方面探讨了Treg/Th17失衡、嘌呤途径在IBD发病中作用，及RARa信号调节嘌呤途径、炎症肠粘膜Treg/Th17平衡、抑制肠道炎症反应的机制。