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

利用ES系衍生的刺疾病模型建立体内系统，评估鼠多基因双酶模型中负责基因的重要性

• 批准号: 18390126
• 负责人: NISHIMURA Hiroyuki
• 金额: $ 10.07万
• 依托单位: Wakayama Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390126/
• 关键词: gene; immunology

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.

在多基因疾病中，责任基因的鉴定不仅困难，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。本研究试图从多基因疾病小鼠模型中筛选出一个多态性的致病基因，并建立ES系，以获得具有正常等位基因的小鼠。为了达到这一目的，利用了两种模型：MRL lpr小鼠的自身免疫性皮炎和BALB/c小鼠而不是C57 BL/6小鼠的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）小鼠的自身免疫性皮炎的不同频率。假设产生MRL gld小鼠时来自C3 H小鼠的基因是频率的原因。MRL gld小鼠中C3 H小鼠的区域在小鼠1号染色体中确定为38.1至102 cM。由于该区域，发现MRL gld小鼠应该回交更多代以发现“责任基因”。另一方面，从MRL lpr小鼠产生ES细胞系。这些细胞表达与未分化状态一致的差异标记，并且在囊胚注射后保留产生嵌合小鼠的能力，但不分化为生殖细胞。2）胸腺切除的BALB/c小鼠的自身免疫性疾病为了鉴定胸腺切除的BALB/c和C57 BL/6小鼠之间不同频率的自身免疫性疾病的负责基因，假设涉及调节性T细胞的调节基因。在小鼠2号染色体上发现了一个具有多态性的基因，并分别获得了具有C57 BL/c小鼠基因的同源BALB/c小鼠和具有BALB/c小鼠基因的同源C57 BL/c小鼠。这些小鼠的数量扩大，以检查基因在不同频率的自身免疫性疾病中的意义。

项目成果

Involvement of a tissue-specific antibody in skin disorders of murine systemic lupus erythematosus and autoinflammatory diseases

组织特异性抗体参与小鼠系统性红斑狼疮皮肤病和自身炎症性疾病

• 发表时间: 2006
• 期刊: Proc Natl Acad Sci U S A. 103
• 作者: Nishimura H;Strominger JL
• 通讯作者: Strominger JL

Involvement of a tissue-specific antibody in skin disorders of murine systemic lupus erythematosus and autoinflammatory diseases.

组织特异性抗体参与小鼠系统性红斑狼疮皮肤病和自身炎症性疾病。

• 发表时间: 2006
• 期刊: Proc Natl Acad Sci USA. : 103
• 作者: Nishimura H;Strominger JL
• 通讯作者: Strominger JL