1996 Fiscal Year Annual Research Report

転写因子NFkBと疾患における役割に関する研究

Research Project

Project/Area Number	08670184
Research Institution	Nagoya City University
Principal Investigator	岡本尚名古屋市立大学, 医学部, 教授 (40146600)
Keywords	慢性関節リウマチ / がん転移 / NF-kB kinase / シグナル伝達 / レドックス制御 / 後天性免疫不全症候群
Research Abstract	NF-kB (nuclear factor kappa B)は種々のサイトカイン、細胞接着分子、誘導型NO合成酵素、ウイルス(HIV、CMV)などの遺伝子発現を正に調節する転写因子である。本研究では、これらの遺伝子産物が、がん細胞の血管内皮との接着を介して血行性転移、慢性関節リウマチ(RA)などの慢性炎症疾患の成り立ちと維持、後天性免疫不全症候群においてはNF-kBが細胞内に潜状するヒト免疫不全症ウイルスが増殖を開始する際の「引き金」になっていること、など病態形成に主要な役割を演じていることを明らかにした。この結果を受けて、NF-kBに注目し、これらの疾患の成り立ちを分子レベルで理解するための基礎的研究を進めながら、これを制御するための治療法開発を進めた。 (1) NF-kB活性化シグナルとエフェクター分子の分離・同定・遺伝子クローニングNF-kB kinaseの精製をヒトT細胞より行い、精製蛋白より部分ペプチド配列を得た。現在、このアミノ酸配列をもとに遺伝子をクローニングしているところである。 (2) NF-kB関連疾患の解析と治療法の開発:1)慢性関節リウマチ(RA)の病態形成にNF-kBとその標的遺伝子群は主要な役割を演じていることをRA疾患から得た関節滑膜細胞を用いた実験で明らかにした。また、NF-kBの核への移行にThioredoxin (TRX)の核移行が伴うことを初めて明らかにし、TRXによるNF-kBのレドックス制御を確認した。2) NF-kBは血管内皮細胞ではE-selectinの遺伝子発現を制御し、がん細胞の接着を促進しがんの血行転移を促すことを明らかにした。3) NF-kB依存性プロモーターを利用してNF-kB阻害剤のスクリーニング系に用いる組み換え細胞を作成した。4)これらの疾患モデルを用い、NF-kBを標的とすることによって治療的制御が可能であることを示した。

Research Products
(14 results)

All Other

All Publications (14 results)

[Publications] Iida, T.: "Identification of a Gly^<862> to Ser substitution in the type 1 collagen gene from a single sperm." Hum. Reprod.2. 131-134 (1996)
[Publications] Okamoto, T.: "Regulation of NF-_KB and Disease Control : Identification of a novel serine kinase and thioredoxin as effectors for signal transduction pathway for NF-_KB activation." Current Topics in Cellular Regulation.(in press). (1996)
[Publications] Zhen-Qiu Liu.: "Proteolytic processing of nuclear factor kB by calpain in vitro." FEBS Lett.385. 109-113 (1996)
[Publications] Kambe, F.: "Redox regulation of thyroid-transcription factors pax-8 and TTF-1 in vitro." Mol Endocrinol.10. 801-812 (1996)
[Publications] Sakurada, S.: "Induction of cytokines and ICAM-1 by proinflammatory cytokines in primary rheumatoid synovial fibroblats and infibition by N-acetyl-L-cysteine and aspirin." Int. Immunol.8. 1483-1493 (1996)
[Publications] Okamoto, T.: "Oxygen radicals, redox regulation of the NF-_KB sigunaling and disease control by antioxidants. (Review)." Nagoya Medical Journal.40. 175-185 (1996)
[Publications] Kato, T.: "Inhibition of IL-8 induction from rhematoid synovial fibroblasts by treatment with aurothioglucose." Ann Rheum Dis. (in press). (1996)
[Publications] Kira, T.: "2-Glycineamide-5-chlorophenly (2-pyril) ketone, a non-benzodiazepin Tat antagonist is effective against acute and chronic HIV-1 infections in vitro." Antiviral Res.32. 55-62 (1996)
[Publications] Sakurada, S.: "Involvement of vascular endothelial growth factor in Kaposi's sarcoma associated with acquired immunodeficiency syndrome." Jpn. J. Cancer Res.87. 1143-1152 (1996)
[Publications] Shono, T.: "Involvement of a transcription factor NF-_KB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress." Mol. Cell. Biol.16. 4231-4239 (1996)
[Publications] J. P. Merin.: "α-Lipoic acid blocks HIV-1 LTR-dependent expression of hygromycin resistance in THP-1 stable transformants." FEBS Lett.394. 9-13 (1996)
[Publications] Nakano, T.: "Clonal selection of foscarnet-resistant HIV-1 variants in vitro." AIDS Research and Humann Retriviruses.(in press). (1997)
[Publications] Okamoto, T.: "Redox regulation of HIV gene expressior." Proceedings for the conference on the development of antioxidant and chelating drugs for the treatment of environment-associated eiseases, Physical Chemical Biology & Medicine (in press), (1996)
[Publications] Okamoto, T.: "Redox regulation of the NF-_KB sigunaling pathway and disease control." Oxydative Stress and Redox Regulation : Cellular Signaling, Aids, Cancer and Other Diseases. Proceeding for the Symposium on Paris., 4 (1996)

1996 Fiscal Year Annual Research Report

転写因子NFkBと疾患における役割に関する研究

Principal Investigator

岡本 尚 名古屋市立大学, 医学部, 教授 (40146600)

Research Products

[Publications] Iida, T.: "Identification of a Gly^<862> to Ser substitution in the type 1 collagen gene from a single sperm." Hum. Reprod.2. 131-134 (1996)

[Publications] Okamoto, T.: "Regulation of NF-_KB and Disease Control : Identification of a novel serine kinase and thioredoxin as effectors for signal transduction pathway for NF-_KB activation." Current Topics in Cellular Regulation.(in press). (1996)

[Publications] Zhen-Qiu Liu.: "Proteolytic processing of nuclear factor kB by calpain in vitro." FEBS Lett.385. 109-113 (1996)

[Publications] Kambe, F.: "Redox regulation of thyroid-transcription factors pax-8 and TTF-1 in vitro." Mol Endocrinol.10. 801-812 (1996)

[Publications] Sakurada, S.: "Induction of cytokines and ICAM-1 by proinflammatory cytokines in primary rheumatoid synovial fibroblats and infibition by N-acetyl-L-cysteine and aspirin." Int. Immunol.8. 1483-1493 (1996)

[Publications] Okamoto, T.: "Oxygen radicals, redox regulation of the NF-_KB sigunaling and disease control by antioxidants. (Review)." Nagoya Medical Journal.40. 175-185 (1996)

[Publications] Kato, T.: "Inhibition of IL-8 induction from rhematoid synovial fibroblasts by treatment with aurothioglucose." Ann Rheum Dis. (in press). (1996)

[Publications] Kira, T.: "2-Glycineamide-5-chlorophenly (2-pyril) ketone, a non-benzodiazepin Tat antagonist is effective against acute and chronic HIV-1 infections in vitro." Antiviral Res.32. 55-62 (1996)

[Publications] Sakurada, S.: "Involvement of vascular endothelial growth factor in Kaposi's sarcoma associated with acquired immunodeficiency syndrome." Jpn. J. Cancer Res.87. 1143-1152 (1996)

[Publications] Shono, T.: "Involvement of a transcription factor NF-_KB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress." Mol. Cell. Biol.16. 4231-4239 (1996)

[Publications] J. P. Merin.: "α-Lipoic acid blocks HIV-1 LTR-dependent expression of hygromycin resistance in THP-1 stable transformants." FEBS Lett.394. 9-13 (1996)

[Publications] Nakano, T.: "Clonal selection of foscarnet-resistant HIV-1 variants in vitro." AIDS Research and Humann Retriviruses.(in press). (1997)

[Publications] Okamoto, T.: "Redox regulation of HIV gene expressior." Proceedings for the conference on the development of antioxidant and chelating drugs for the treatment of environment-associated eiseases, Physical Chemical Biology & Medicine (in press), (1996)

[Publications] Okamoto, T.: "Redox regulation of the NF-_KB sigunaling pathway and disease control." Oxydative Stress and Redox Regulation : Cellular Signaling, Aids, Cancer and Other Diseases. Proceeding for the Symposium on Paris., 4 (1996)

岡本尚名古屋市立大学, 医学部, 教授 (40146600)