Analysis of pathogenicity and development of novel therapy byinflammation-regulating proteins in systemic autoimmune diseases

系统性自身免疫性疾病的致病性分析及炎症调节蛋白新疗法的开发

• 批准号: 22390201
• 负责人: MIMORI Tsuneyo
• 金额: $ 11.98万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22390201/
• 关键词: カルパイン; カルパスタチン; FRP; Th17 細胞; 自己抗体; 関節リウマチ; 自己免疫疾患; フォリスタチン関連蛋白; 炎症性ｻｲﾄｶｲﾝ; T細胞分化; サイトカイン; 破骨細胞

We reported previously that autoantibodies to calpastatin (inhibitor of calpain (calcium-dependent neutral proteinase)) and follistatin-related protein (FRP) are found in patients with rheumatoid arthritis. Since these target antigens appeared to show regulatory effects against inflammation, we have intended to clarify the possibility that arthritis may be treated by regulating these autoantigens and autoantibodies. Calpastatin inhibited not only the secretion of IL -6 from fibroblasts, but also affected T cell differentiation, in particular strongly suppress ed the differentiation and activation of Th17 cell. Although FRP has been debated to show different action on regulating of inflammation between human and mouse, we demonstrated that FRP activates inflammation in natural immunity system via TLR4 -CD14 signaling. Analyses of these inflammation-regulating proteins may clarify the pathogenic mechanisms and novel therapeutic strategies of inflammatory arthritis and autoimmune diseases

我们之前曾报道，类风湿性关节炎患者中发现抗钙素(钙蛋白酶(钙依赖中性蛋白酶)的抑制剂)和卵泡抑素相关蛋白(FRP)的自身抗体。由于这些靶抗原似乎显示出抗炎的调节作用，我们打算澄清通过调节这些自身抗原和自身抗体来治疗关节炎的可能性。Calastatin不仅抑制成纤维细胞分泌IL-6，还影响T细胞的分化，尤其是强烈抑制Th17细胞的分化和活化。尽管FRP在人和小鼠的炎症调节中显示了不同的作用，但我们证明了FRP通过TLR4-CD14信号在自然免疫系统中激活炎症。对这些炎症调节蛋白的分析可以阐明炎症性关节炎和自身免疫性疾病的发病机制和新的治疗策略。

项目成果

DIP2 disco-interacting protein 2 homolog A (Drosophilla) is a candidate receptor for follistatin-related protein/follistatin-like 1. Analysis of their binding with TGF-β superfamily proteins.

DIP2 disco 相互作用蛋白 2 同源物 A（果蝇）是卵泡抑素相关蛋白/卵泡抑素样 1 的候选受体。分析其与 TGF-β 超家族蛋白的结合。

• 发表时间: 2010
• 期刊: FEBS J
• 影响因子: 5.4
• 作者: Tanaka M;Mimori T;et al(16人中16人目)
• 通讯作者: et al(16人中16人目)

Aberrant splicing of milk fat globule EGF factor 8 gene in human systemic lupus erythematosus.

人类系统性红斑狼疮乳脂肪球 EGF 因子 8 基因的异常剪接。

• 发表时间: 2010
• 期刊: Eur.J.Immunol.
• 作者: Yamaguchi H.;et al.
• 通讯作者: et al.

Complement drives Th17 cell differentiation and triggers autoimmune arthritis.

• DOI: 10.1084/jem.20092301
• 发表时间: 2010-06-07
• 期刊: The Journal of experimental medicine
• 作者: Hashimoto M;Hirota K;Yoshitomi H;Maeda S;Teradaira S;Akizuki S;Prieto-Martin P;Nomura T;Sakaguchi N;Köhl J;Heyman B;Takahashi M;Fujita T;Mimori T;Sakaguchi S
• 通讯作者: Sakaguchi S