Development of therapy for malignant tumors and inflammatory diseases employing midkine as a molecular target

以中期因子为分子靶标的恶性肿瘤和炎症性疾病治疗方法的开发

• 批准号: 15390103
• 负责人: MURAMATSU Takashi
• 金额: $ 9.79万
• 依托单位: Aichi Gakuin University (2004)Nagoya University (2003)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390103/
• 关键词: midkine; Anti-cancer drug; renal toxicity; knockout mice; neutrophils; tumor metastasis; endothelial cells; antisense oligo DNA; リウマチ; アルツハイマー病; 新生内膜形成; 炎症性細胞; 癒着; マクロファージ

Midkine played important roles in renal injury caused by ischemia or chemotherapeutic reagent. Promotion of migration of inflammatory leukocytes was the primary mechanism of midkine action. We injected midkine antisense oligo DNA to tail vein of mice to suppress midkine expression. The oligo DNA was actively taken up by renal tubular epithelial cells. When oligo DNA was injected before ischemia or drug administration, migration of inflammatory leukocytes to renal tubules was significantly suppressed. Sense oligo DNA did not exhibited the effects. Furthermore, renal damage by ischemia was indeed lessened by the oligo DNA treatment. Neointima formation after injury was also lessened by prior treatment with the antisense oligo DNA.The involvement of midkine in adhesions after surgery and arthritis after injection of anti-type II collagen, a model of rheumatoid arthritis. was shown by using mice deficient in the midkine gene. In both cases, promotion of migration of inflammatory leukocytes is involved ; in addition midkine promoted differentiation of osteoclasts in the case of arthritis.We developed antisense oligo DNA and siRNA to suppress the expression of human midkine. We also found that atelocollagen helped both stabilization and incorporation of siRNA, and verified the effects by suppressing VBGF expression leading to the growth suppression of nude-mice grown human tumors. The involvement of midkine in host blood vessels in tumor metastasis was demonstrated by using mice deficient in the midkine gene.

中期因子在缺血或化疗药物引起的肾损伤中发挥重要作用。促进炎症白细胞迁移是中期因子作用的主要机制。我们将中期因子反义寡DNA注射到小鼠尾静脉以抑制中期因子表达。寡聚DNA被肾小管上皮细胞主动吸收。当在缺血或给药前注射寡聚DNA时，炎性白细胞向肾小管的迁移被显着抑制。有义寡聚DNA没有表现出这种效果。此外，寡DNA治疗确实减轻了缺血引起的肾损伤。损伤后新内膜的形成也通过反义寡DNA的预先治疗而减少。中期因子参与手术后粘连和注射抗II型胶原蛋白后的关节炎（类风湿性关节炎模型）。通过使用缺乏中期因子基因的小鼠来证明。在这两种情况下，都涉及促进炎症白细胞的迁移；此外，在关节炎的情况下，中期因子可促进破骨细胞的分化。我们开发了反义寡DNA和siRNA来抑制人中期因子的表达。我们还发现去端肽胶原有助于 siRNA 的稳定和掺入，并通过抑制 VBGF 表达从而抑制裸鼠生长的人类肿瘤的生长来验证其效果。通过使用缺乏中期因子基因的小鼠证明中期因子参与宿主血管中的肿瘤转移。

项目成果

Midkine, a heparin-binding growth factor, is fundamentally involved in pathogenesis of rheumatoid arthritis

Midkine 是一种肝素结合生长因子，从根本上参与类风湿性关节炎的发病机制

• 发表时间: 2004
• 期刊: Arthritis Rheum. 50
• 作者: Maruyama;S. et al.
• 通讯作者: S. et al.

Midkine, a heparin-binding growth factor, produced by the host enhances metastasis of Lewis lung carcinoma cells

• DOI: 10.1016/j.canlet.2005.02.047
• 发表时间: 2006-02-20
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Salama, RHM;Muramatsu, H;Muramatsu, T
• 通讯作者: Muramatsu, T

Antisense oligodeoxyribonucleotide as to the growth factor midkine suppresses neointima formation induced b balloon injury

生长因子中期因子的反义寡脱氧核糖核苷酸抑制 b 球囊损伤引起的新内膜形成

• 期刊: Am.J.Physiol.Heart Circ.Physiol. (in press)
• 作者: Hayashi;K. et al.
• 通讯作者: K. et al.

Antisense oligodeoxyribonucleotide as to the growth factor midkine suppresses neointima formation induced by balloon injury

• DOI: 10.1152/ajpheart.00555.2004
• 发表时间: 2005-05-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
• 影响因子: 4.8
• 作者: Hayashi, K;Banno, H;Muramatsu, T
• 通讯作者: Muramatsu, T

Tomizawa, M.: "A promoter region of the midkine gene that is frequently expressed in human hapatocellular carcinoma can activate a suicide gene as effectively as the α-fetoprotein promoter"Br.J.Cancer. 89. 1086-1090 (2003)

Tomizawa, M.：“在人肝细胞癌中频繁表达的中期因子基因的启动子区域可以像甲胎蛋白启动子一样有效地激活自杀基因”Br.J.Cancer. 89. 1086-1090 (2003)