利用基因敲除小鼠研究Graves'病相关基因GPR174对免疫调控及疾病易感性的影响与机制

Graves'病是一种女性高发的自身免疫性疾病。在前期Graves'病遗传机制的研究过程中，我们用改进的计算方法分析了全基因组关联研究中X染色体的数据，发现GPR174基因与Graves'病易感性显著相关，并且关联程度仅次于HLA基因。进一步的重测序研究显示，GPR174基因上存在一些罕见变异也与Graves'病相关。表达研究显示，此基因广泛的表达于免疫相关组织。有可能在Graves'病的发病过程中起重要作用。GPR174基因是一个位于G蛋白偶联受体基因，目前对其功能所知甚少，最近要研究报道其配体为LysoPS。有可能成为潜在的药靶。本项目通过构建GPR174基因敲除小鼠，研究GPR174在免疫调控中的作用；并对基因敲除小鼠和野生型小鼠进行转录组测序，发现GPR174的信号传导通路。系统阐述GPR174对Graves'病发病机制的影响，为Graves'治疗新药物的病发现奠定基础。

Graves' disease is a female-predominant organ-specific autoimmune disease. In our previous study of genetic mechanism for Graves' disease, we re-analyzed the X chromosome from our recent genome-wide association study. The GPR174 gene was found associaiton with susceptibility of Graves' disease, and the significance of association was next to the HLA region. Further resequecing analysis revealed some rare variants of GPR174 were also contributed to disease risk. And our expression experiment found that GPR174 was widely expressed in human immune-related tissues and organs. These result indicated that GPR174 might play an important role in the pathogenesis of Graves' disease. GPR174 is a G protein coupled receptor, little was known about its physiological function. Very recently, LysoPS was reported as the receptor of GPR174. GPR174 might be a potential therapeutic target. In this project, we will investigated the function of immune regulation for GPR174 using GPR174 deficency mice. In order to identified the signal transduction pathway in which GPR174 was involved, we will study the difference of expression pattern of GPR174 deficency mice and the wild type mice utilizing RNAseq.Based on these research, we will clarify the influence of GPR174 on the pathogenesis of Graves' disease and lay the foundation for the identification of new therapeutic drug for Graves' disease.