Gpr97在炎症应答中的作用及分子机制的研究

NF-κB信号通路的严密调控是固有免疫和适应性免疫应答所必需的，然而其负调控的分子机制尚不清楚。Gpr97是一个主要在免疫细胞表达的孤儿G蛋白偶联受体。课题组为研究该基因在免疫系统中的作用及其机制，建立了Gpr97基因剔除小鼠模型。表型分析表明Gpr97在B细胞发育过程中起到不可或缺的作用。此外相关分子机制研究显示，Gpr97缺失显著增加脾脏组织核提取物中的cAMP反应元件结合蛋白的磷酸化水平，且促进p50和p65蛋白的入核。这强烈提示该基因在NF-κB信号通路中的起到重要的调节作用。本项目将利用该基因剔除小鼠模型研究Gpr97在TLR依赖和非依赖的免疫反应中的作用，阐明Gpr97调控TLR信号通路和NF-κB的分子机制。这些研究结果能够帮助我们进一步了解Gpr97的生物学功能及其如何调控炎症反应的发生，而且在此基础之上有望为影响我国人民健康的感染性疾病的治疗提供理论基础和新的药物靶点。

Tight regulation of NF-kB signaling is essential for innate and adaptive immune responses, yet the molecular mechanisms responsible for its negative regulation are not completely understood. Gpr97, an orphan adhesion GPCR, is highly expressed in immune cells. To explore the function of Gpr97 in immune system and the molecular mechanism involved, we generated a mouse model with global-targeted deletion of Gpr97. The phenotypic analyses have demonstrated an indispensable role of Gpr97 in maintaining B-lymphocyte population. By screening for the molecular events involved in the observed phenotypes, we found that lambda 5 expression is downregulated and its upstream inhibitor Aiolos is increased in the spleen of mutant mice, accompanied by significantly enhanced phosphorylation and nuclear translocation of cAMP response element-binding protein. Interestingly, increased constitutive NF-κB p50/p65 expression and activity were observed in the spleen of mutant mice, implicating a crucial role of Gpr97 in regulating NF-κB activity. In this project, we will make use of the Gpr97 knockout mouse model to characterize a role for Gpr97 in TLR-dependent or independent inflammatory responses. Furthermore, we attempt to identify the underlying mechanism(s) by which Gpr97 controls the inflammation. Results from these studies not only reveal more insights into the regulatory mechanism of innate immune system, but also provide useful target for manipulating amount responses against infections or inflammation-associated diseases, including cancer.