Analysis of regulation of host defense response by osteopopontin and its applocation to diagnosis and therapy strategy

骨桥蛋白对宿主防御反应的调节分析及其在诊断和治疗策略中的应用

• 批准号: 10557024
• 负责人: UEDE Toshimitsu
• 金额: $ 7.1万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10557024/
• 关键词: osteopontin; cancer; prognosis; atherosclerosis; 肉芽腫; アレル; トランスジェニックマウス; iNOS; ELISA; CD44v; β1インテグリン; 細胞接着; 細胞遊走; 転移

1. Highly metastatic adenocarcinoma cells tend to secrete osteopontin(OPN). OPN binds to β1 integrin-containing receptors in an autocrine fashion and induce motility of tumor cells. The association of β1 integrins with CD44v on tumor cell surface is essential for OPN-induced tumor cell motility.2. The new-vessel formation as defined by CD34 positive endothels was significantly increased in OPN and VEGF positive stage I lung adenocarcinoma tissues and corelated very well with poor prognosis of patients.3. Upon high fat diet feeding, OPN transgenic mice developed considerably severe atherosclerosis as compared to control mice. In OPN transgenic mice, macrophages within atherosclerotic lesions expressed significant levels of OPN.4. Upon intravenous injection of zymosan, mice develoved liver granuloma, the development of granuloma was significantly inhibited by simultaneous injection of anti-OPN antibody, indicating the critical role of OPN in the granuloma development.

1.高转移腺癌细胞倾向于分泌骨桥蛋白(OPN)。OPN以自分泌方式与β-1整合素受体结合，诱导肿瘤细胞运动。结论：1.β-1整合素与肿瘤细胞表面CD44v的结合是骨桥蛋白诱导肿瘤细胞运动所必需的。CD34阳性内皮细胞定义的新血管生成在OPN和VEGF阳性的I期肺腺癌组织中显著增加，且与患者预后不良密切相关。在高脂饲料喂养下，OPN转基因小鼠与对照小鼠相比，出现了相当严重的动脉粥样硬化。在OPN转基因小鼠中，动脉粥样硬化病变内的巨噬细胞表达显著水平的OPN.4。静脉注射酵母多糖诱导小鼠肝肉芽肿形成后，同时注射抗OPN抗体可显著抑制肉芽肿的形成，提示OPN在肉芽肿形成中起关键作用。

项目成果

J.Iizuka, Y.Katagiri, N.Tada, M.Murakami, T.Ikeda, M.Sato, K.Hirokawa, S.Okada, M.Hatano, T.Tokuhisa, T.Uede: "Introduction of an osteopontin gene confers the increase in B1 cell population and the production of anti-DNA autoantibodies."Lab.Invest.. 78(12

J.Iizuka、Y.Katagiri、N.Tada、M.Murakami、T.Ikeda、M.Sato、K.Hirokawa、S.Okada、M.Hatano、T.Tokuhisa、T.Uede：“骨桥蛋白基因的介绍

T.Fukumoto: "Peptide mimics of the CTLA4-binding domain stimulate T-cell proliferation."Nat.Biotechnol.. 16(3). 267-270 (1998)

T.Fukumoto：“CTLA4 结合域的肽模拟物刺激 T 细胞增殖。”Nat.Biotechnol.. 16(3)。

T.Takahashi: "Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4."J.Exp.Med.. 192(2). 303-310 (2000)

T.Takahashi：“通过持续表达细胞毒性 T 淋巴细胞相关抗原 4 的 CD25( )CD4( ) 调节性 T 细胞维持免疫自我耐受。”J.Exp.Med. 192(2)。

Y. Katagiri: "CD44 variants but not CD44s cooperate with β1-containing integrins to permit cells to bind to osteopontin independently of arginine-glycine-aspartic acid, thereby stimulating cell motility and chemotaxis"Cancer Res.. 59(1). 219-226 (1999)

Y. Katagiri：“CD44 变体而非 CD44 与含有 β1 的整联蛋白配合，允许细胞独立于精氨酸-甘氨酸-天冬氨酸与骨桥蛋白结合，从而刺激细胞运动和趋化性”Cancer Res.. 59(1)。 226（1999）

M.Takemoto, K.Yokote, M.Nishimura, T.Shigematsu, T.Hasegawa, S.Kon, T.Uede, T.Matsumoto, Y.Saito, S.Mori: "Enhanced expression of osteopontin in human diabetic and analysis of its functional role in accelerated atherogenesis."Arterioscler. Throm.Vasc.Biol

M.Takemoto、K.Yokote、M.Nishimura、T.Shigematsu、T.Hasekawa、S.Kon、T.Uede、T.Matsumoto、Y.Saito、S.Mori：“人类糖尿病中骨桥蛋白的增强表达和分析