粘附G蛋白偶联受体GPR97对EAE发病的影响及其机制

近年来大量研究显示G蛋白偶联受体（GPCR）可以通过调节免疫细胞的功能而参与多发性硬化症（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）的发病。GPR97属于一种粘附GPCR，在免疫细胞中广泛表达。我们前期的研究结果显示GPR97基因敲除可加重EAE发病，而且GPR97对树突状细胞（DC）的分化及功能具有负向调节作用，但其机制有待阐明。本研究拟利用GPR97基因敲除小鼠或条件性敲除小鼠为研究对象，以骨髓来源的DC和EAE小鼠脾细胞或中枢神经系统（CNS）中分离的DC为细胞模型，从基因敲除和激动剂激活两个方面，在动物、细胞和分子水平系统地探讨GPR97及其激动剂二丙酸倍氯米松（BDP）对树突状细胞的分化和功能的调控作用及其信号通路，明确GPR97参与EAE的发病机制，探讨以GPR97为靶点进行EAE治疗的可行性，从而为阐明MS发病新机制和为MS治疗提供潜在药物靶点奠定实验基础。

A number of studies have shown that G protein-coupled receptors (GPCRs) take part in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) by regulating the function of immune cells. GPR97 belongs to a kind of adhesion GPCR and it widely expresses in immune cells. Our previous data showed that knockout of GPR97 could aggravate the pathogenesis of EAE and GPR97 might have negative immunoregulation on the differentiation and function of DCs. Nevertheless, the mechanism remains undefined. Based on the previous work from our group, GPR97-KO or conditional GPR97-KO mice will be used as the object of study, bone marrow-derived DCs and the isolated DCs from spleen or central nervous system (CNS) in naïve or EAE mice will be used as the cell model, whether GPR97 and its agonist BDP can affect the differentiation and function of DCs and its signal transduction mechanism will be studied from the two sides of gene deficiency and agonist activation at the levels of animal, cell and molecule, and the pathogenesis of EAE will be elucidated and the possibility of using GPR97 as the therapeutic target against EAE will be analyzed. The study will provide experimental basis on the elucidation of the novel pathogenesis of MS and development of potential drug target for MS.