The establishment of an in vivo system estimating the significance of a responsible gene for murine polygenic dianase model by using ES lines derived thorn the disease model

在多基因疾病中，识别负责基因不仅困难，而且证明候选基因在体内的重要性的实验系统还没有很好地建立。在本报告中，我们试图找出一个具有多态性的负责基因，并从多基因小鼠疾病模型中建立ES系，以产生具有正常等位基因基因的小鼠。为了达到这一目的，我们利用了两种模型：MRL LPR小鼠的自身免疫性皮炎和BALB/c而不是C57BL/6小鼠胸腺切除后的自身免疫性疾病1)MRL LPR小鼠的自身免疫性皮炎我们注意到MRL LPR(Fas受体缺陷)和MRL GLD(其配体缺陷)小鼠自身免疫性皮炎的发生率不同。来自C3H小鼠的基因被假设为产生MRL GLD小鼠的频率的原因。在小鼠1号染色体38.1~102 cM范围内，确定了MRL GLD小鼠的C3H基因区域。由于该区域的存在，发现MRL GLD小鼠需要回交更多世代才能发现其负责基因。另一方面，从MRL LPR小鼠中获得ES细胞系。2)去胸腺BALB/c小鼠的自身免疫性疾病为BALB/c小鼠的自身免疫性疾病，为确定BALB/c和C57BL/6小鼠不同频率自身免疫性疾病的致病基因，推测与调节性T细胞的调节基因有关。我们在小鼠2号染色体上发现了一个具有多态性的基因，并产生了与C57BL/c小鼠基因相同的BALB/c小鼠和与BALB/c小鼠基因相同的C57BL/c小鼠。这些小鼠的数量被扩大，以检查该基因在不同频率的自身免疫性疾病中的意义。

In polygenic disorders, the identification of a responsible gene is not only difficult but experimental systems to demonstrate the significance of the candidate gene in vivo has not yet been well established. In this report, we tried to identify a responsible gene with a polymorphism and to establish ES lines from polygenic mouse disease model to generate a mouse with the genes of normal alleles. To achieve this goal, two models were utilized: autoimmune dermatitis in MRL lpr mice and autoimmune diseases after thymectomized BALB/c but not C57BL/6 mice.1) Autoimmune dermatitis in MRL lpr miceWe paid attention to the different frequency of autoimmune dermatitis between MRL lpr (FAS receptor deficient) and MRL gld (its ligand deficiency) mice. Genes from C3H mice as MRL gld mice were generated were hypothesized to be responsible for the frequency. The region of C3H mice in MRL gld mice was determined between 38.1 and 102 cM in mouse chromosome 1. Because of the region, it was found that MRL gld mice should be backcrossed more generations to discover' responsible genes. On the other hand, ES cell lines were generated from MRL lpr mice. These cells expressed differential markers consistent with undifferentiated state and retained capability of generating chimeric mice after blastcyst injection but not of differentiating into germ cells.2) Autoimmune diseases in thymectomized BALB/c miceTo identify a responsible gene for different frequency of autoimmune diseases between thymectomized BALB/c and C57BL/6 mice, regulator genes for regulatory T cells were hypothesized to be involved. We found a gene with polymorphism in mouse chromosome 2 and generated a congenic BALB/c mice with the gene of C57BL/c mice and a congenic C57BL/c mice with the gene of BALB/c mice. These mice were expanded in number to examine the significance of the gene in the different frequency of autoimmune diseases.