Establishment of a novel recombinant inbred strain of mice MXH/lpr with genetic dissociation of the complex pathological and pathophysiological phenotypes of collagen disease under a polygene network

建立新型重组近交系小鼠 MXH/lpr，在多基因网络下对胶原病的复杂病理和病理生理表型进行遗传分离

• 批准号: 18390123
• 负责人: NOSE Masato
• 金额: $ 10.17万
• 依托单位: Ehime 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-18390123/
• 关键词: collagen disease; recombinant inbred strain; SDP table; autoantibody; protein synthesis in cell free system; AlphaScreen method; TLR3; inflammatory cytokines; SNPs; 環境要因; poly I:C; ポリジーン; MRL; 1pr; MXH

Category of collagen disease has been defined as a syndrome overlapping connective tissue diseases, rheumatic diseases and autoimmune or immunological disorders. However, the genetic basis of collagen disease remains unclear. The MRL/MpJ-lpr/lpr (MRL/lpr) strain of mice spontaneously develop glomerulonephritis, systemic vasculitis, polyarthritis and sialoadenitis, thus resembling lupus nephritis, polyarteritis nodosa, rheumatoid arthritis and Sjogren's syndrome, respectively, associated with the high titers of various autoantibodies. These findings suggest that this stain should be used as a collagen disease model. In this study, we established a novel recombinant inbred strain of mice MXH/lpr composed of 15 lines by intercrosses of MRL/lpr and non-collagen disease-prone strain of mice C3H/HeJ-lpr/lpr. First, we determined polymorphic microsatellite markers and SNPs on total chromosomes of these lines to establish a strain distribution pattern table. And, we prepared the data base of s … More equential changes of histopathological phenotypes of glomerulonephritis, vasculitis, arthritis and sialoadenitis of each line with quantitatively scoring of the lesions, focusing their onset and progression stages. Then, the candidates of quantitative trait loci for each lesion were determined. Moreover, we examined the expression profiles of autoantibodies against the synthetic proteins prepared by cell free system based on the genome data base of susceptibility loci to all lesions in the AlphaScreen method. Among them, we identified the autoantibodies closely associated with the development of the lesions. Finally, to simulate the influence of environmental factors to collagen disease phenotypes in relation with their genomic polymorphism, we injected poly I: C to each line of the RI strain and analyzed the host responses via TRL3 signaling. We found a regular variation of histopathological phenotypes among the RI lines, especially causing pancreatitis in one line. Furthermore, we established a data base of the expression profiles of inflammatory cytokines in the RI strain. In conclusion, from these results by using a novel recombinant inbred strain of mice MXH/lpr, we learned that the complex pathological pathophysiological phenotypes of collagen disease can be genetically dissected and modified by particular environmental factors which are under the control a polygene network system. Our RI strain will be an important tool to further study the relationship between genome and environmental factors in collagen disease. Less

胶原病的类别被定义为与结缔组织疾病、风湿性疾病和自身免疫或免疫性疾病重叠的综合征。然而，胶原病的遗传基础仍不清楚。 MRL/MpJ-lpr/lpr (MRL/lpr)品系小鼠自发发生肾小球肾炎、系统性血管炎、多发性关节炎和唾液腺炎，因此分别类似于狼疮性肾炎、结节性多动脉炎、类风湿性关节炎和干燥综合征，与各种自身抗体的高滴度相关。这些发现表明该染色剂应用作胶原蛋白疾病模型。在本研究中，我们通过 MRL/lpr 与非胶原蛋白疾病倾向小鼠品系 C3H/HeJ-lpr/lpr 杂交，建立了由 15 个品系组成的新型重组自交系小鼠 MXH/lpr。首先，我们确定了这些品系总染色体上的多态性微卫星标记和SNP，以建立菌株分布模式表。并且，我们准备了每个系的肾小球肾炎、血管炎、关节炎和唾液腺炎的组织病理学表型的连续变化的数据库，并对病变进行定量评分，重点关注其发病和进展阶段。然后，确定每个病变的候选数量性状位点。此外，我们根据AlphaScreen方法中所有病变易感位点的基因组数据库，检查了无细胞系统制备的针对合成蛋白的自身抗体的表达谱。其中，我们鉴定了与病变发展密切相关的自身抗体。最后，为了模拟环境因素对胶原蛋白疾病表型及其基因组多态性的影响，我们向 RI 菌株的每个品系注射了 Poly I:C，并通过 TRL3 信号传导分析了宿主反应。我们发现 RI 系之间的组织病理学表型有规律的变化，尤其是在一个系中引起胰腺炎。此外，我们建立了 RI 菌株中炎症细胞因子表达谱的数据库。总之，通过使用新型重组近交系小鼠 MXH/lpr，从这些结果中，我们了解到胶原蛋白疾病的复杂病理病理生理表型可以通过多基因网络系统控制下的特定环境因素进行基因剖析和修改。我们的 RI 菌株将成为进一步研究胶原蛋白疾病中基因组与环境因素之间关系的重要工具。较少的

项目成果

Cappuccino mutation in an autoimmune-prone strain of mice suggests a role of platelet function in the progression of immune complex crescentic glomerulonephritis.

• DOI: 10.1002/art.22059
• 发表时间: 2006-09
• 期刊: Arthritis and rheumatism
• 作者: Minako Yoshida;K. Saiga;T. Hato;Shoko Iwaki;T. Niiya;N. Arita;H. Komori;T. Tsubaki;H. Furukawa;M. Terada;K. Maeyama;K. Nemoto;M. Nose;M. Ono

Antagonist of interferon-inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice

• DOI: 10.1002/art.21745
• 发表时间: 2006-04-01
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Hasegawa, H;Inoue, A;Yasukawa, M
• 通讯作者: Yasukawa, M

Persistent expression of an unproductive immunoglobulin heavy chain allele with D_H-J_H-γ configuration in peripheral tissues

外周组织中具有 D_H-J_H-γ 构型的非生产性免疫球蛋白重链等位基因的持续表达

• 发表时间: 2007
• 期刊: APMIS 115(12)
• 作者: Ono M;Nose M
• 通讯作者: Nose M

Increased expression of soluble form of vascular cell adhesion molecule-1 aggravates autoimmune arthritis in MRL-Fas^<1pr> mice

MRL-Fas^<1pr> 小鼠中可溶形式血管细胞粘附分子-1 表达增加加重自身免疫性关节炎

• 发表时间: 2007
• 期刊: Pathology International 57(11)
• 作者: Oishi;H;Mizuki;S;Terada;M;Kubo;M;Araki;K;Araki;M;Nose M;Takahashi;S
• 通讯作者: S

Dominrnant resistant loci to lupus nephritis involving CD59a in a wild type mice-derived inbred strain MSM/Ms

野生型小鼠自交系 MSM/Ms 中涉及 CD59a 的狼疮肾炎显性耐药位点

• 发表时间: 2006
• 作者: Lu LM;Nakatani K;Terada M;Miyazaki T;Nose M;et. al.
• 通讯作者: et. al.