| Project/Area Number |
12671146
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | Tokyo Medicai and Dental University |
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Principal Investigator |
YAMAGUCHI Noriko Tokyo Medicai and Dental University, Med. Res. Inst., Dept. of Mol. Pathogenesis, Res. Assoc., 難治疾患研究所, 助手 (90251553)
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| Co-Investigator(Kenkyū-buntansha) |
HORI Hisae Tokyo Medicai and Dental University, Med. Res. Inst., Dept. of Mol. Pathogenesis, Res. Assoc., 難治疾患研究所, 助手 (80014190)
OKABE Satoshi Tokyo Medicai and Dental University, Graduate School, Dept. of Digestive Surgery, Lecturer, 大学院・医歯学総合研究科, 講師 (60242187)
AOYAGI Masaru Tokyo Medicai and Dental University, Graduate School, Dept. of Neurosurgery, Assoc. Prof., 大学院・医歯学総合研究科, 助教授 (40134704)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2000: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | Angiogenesis / Endostatin / Tumor / Cancer / Collagen |
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| Research Abstract |
Endostatin is a fragment derived from type XVIII collagen which constitutes blood vessel basement membrane, showed strong antiangiogenic activity and suppressed tumor growth. The phase II clinical study of Endostatin is performing as anti-cancer drug in USA. However, functional mechanism of endostain/collagen XVIII is still unknown. Our research goal is to analyze molecular mechanisms of action of endostatin on suppression of tumor growth, invasion and metastasis. In parallel, we estimated the efficacy of endostatin in tumor animal model.
1. For isolation of endostatin receptor, the binding fraction was prepared by edostatin-immobilized affinity column. A couple of proteins in the fraction were subjected to amino acid sequencing, but we cold not obtain any data. Now we are preparing peptide fragments by enzyme digestion and analyzing amino acid sequence of these fragments.
2. Endostain showed inhibitory activity of migration of endothelial cell induced by growth factor, VEGF. It is not clear the affect of endostain in signal transduction passway induced by VEGF. But we found that endostatin itself induced weak phosphorylation of MAP kinase and planed to investigate the competition of MAP kinase activation.
3. To localize the active site of endostatin, mutants having amino acid substitution were prepared and compared to wild type. The active site was successfully localized the region of molecular surface. The synthetic peptide covered the region failed to show comparable activity of endostain. The new peptides covering slightly different region are prepared and the possibility of structural contribution to activity is examined.
4. In animal model that has brain tumor, the recombinant endostatin regress the tumor volume to one fourth. The approach of gene therapy using plasmid DNA coding endostain was launched.
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