Grant-in-Aid for Co-operative Research (A)
|Allocation Type||Single-year Grants|
|Research Institution||HIROSHIMA UNIVERSITY|
KURAMOTO Atsushi Research Institute for Radiation Biology and Medicine, Hiroshima University Professor, 原爆放射能医学研究所, 教授 (50034070)
SAITO Hidehiko Nagoya Univ.Shool of Med.Professor, 医学部, 教授 (20153819)
OKUMA Minoru Kyoto Univ.Faculty of Med.Int.Med.Professor, 医学部, 教授 (50026986)
IWANAGA Sadaaki Kyushu Univ.Faculty of Science Professor, 理学部, 教授 (90029942)
TITANI Koichi Fujita Health Univ.shool of Med.Professor, 総合医科学研究所, 教授 (60179942)
SUZUKI Koji Mie Univ.Faculty of Med.Molecular Boil.Professor, 医学部, 教授 (70077808)
青木 延雄 東京医科歯科大学, 医学部, 教授 (20048937)
|Project Period (FY)
1993 – 1994
Completed(Fiscal Year 1994)
|Budget Amount *help
¥37,100,000 (Direct Cost : ¥37,100,000)
Fiscal Year 1994 : ¥17,200,000 (Direct Cost : ¥17,200,000)
Fiscal Year 1993 : ¥19,900,000 (Direct Cost : ¥19,900,000)
|Keywords||regulator of coagulation factor / gene therapy / gene analysis / platelet membrane receptor / extrinsic coagulation pathway / apolipoprotein / NF-KB / thransfer treatment of antisense ligomer / 凝固線溶調節因子欠損症 / エンドトキシンショック / 血小板膜レセプター異常症 / レセプター機能ドメイン / vWF活性化因子 / 遺伝子組み換え技術 / 遺伝子解析 / アンチセンス療法|
The fundamental investigation for gene therapy and molecular biological analysis to regulation factor of thrombin, coagulation factor and apoprotein system, platelet membrane receptor, and endothelial systems progressed as follows.
1.The gene analysis of protein C,protein S and alpha2-plasmin inhibitor abnormalities or deficiency which repeat thrombosis, and the hereditary platelet functional abnormalities include the Bernard-Soulier syndrome(BSS), adhesion function deficinecy due to the low expression or defect of GPIb/IX-V and thromboxan A2 receptor abnormalites which show the bleeding tendency were studied.
These studies have made clear the functional abnormality sites of these coagulation regulation factors or receptors and the mechanism of secretion abnormalities or receptor expression deficiency of these diseases.
The specific functional domain of GPIIb/IIIa(fibrinogen receptor)for fibrinogen binding was explained by using recombinant gene technology.
These researches will contribute
the explanation of target for gene therapy of these hereditary disease, the production of recombinant protein with high quality and function and the development of new anti thrombotic agents.
2.The interaction domain between coagulation factor VII and tissue factor(TF)in extrinsic coagulation pathway and the transcription mechanism of apolipoprotein gene were examined. These studies will link into the therapy for prevention of thrombosis.
3.The inflammatory cytokines which were secreted from endothelial cells by the stimulation of endotoxin, thrombin or TNF and the proliferation of endothelial smooth muscle cells by thrombin were important factor for the development of atherosclerosis and thrombosis.
The secretion of the inflammatory cytokines and the proliferation of smooth muscle cells were induced by the transcription factor NF-KB.On the other hand, these reactions were inhibited by transfer the antisense NF-KB oligomer to endothelial cells. This sntisense therapy explained the effectiveness for the prevention of atherosclerosis, thrombosis and the development of DIC. Less