| Project/Area Number |
08557148
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | NATIONAL CHILDREN'S MEDICAL RESEARCH CENTER |
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Principal Investigator |
TSUJIMOTO Gozoh National Children's Medical Research Center, Director, 小児医療研究センター・小児薬理研究部, 部長 (80172013)
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| Co-Investigator(Kenkyū-buntansha) |
TAKADA Tatsuyuki National Children's Medical Res. Center, Researcher, 小児医療研究センター・小児薬理研究部, 重点研究支援協力員
TAKEI Yoshinori National Children's Medical Res. Center, Researcher, 小児医療研究センター・小児薬理研究部, 重点研究支援協力員
HIRASAWA Akira National Children's Medical Res. Center, Researcher, 小児医療研究センター・小児薬理研究部, 研究員 (70242633)
ITO Shuji OTSUKA PHARMACEUTICAL CO., LTD., 2ND TOKUSHIMA INSTITUTION OF NEW DRUG RESEARCH, RESEARCHER, 徳島新薬第二研究所, 研究員
殊才 孝則 大塚製薬株式会社, 徳島研究所, 研究員
片岡 正和 国立小児病院, 小児医療研究センター・小児薬理研究部, 科学技術庁重点研究支
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| Project Period (FY) |
1996 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥18,100,000 (Direct Cost: ¥18,100,000)
Fiscal Year 1998: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1997: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1996: ¥15,000,000 (Direct Cost: ¥15,000,000)
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| Keywords | G-protein-coupled receptor / alpha1-adrenoceptor subtypes / cellular signal transduction mechanism / molecular cloning / visualized cell biology / conforcal microscopy / intracellular localization / サブタイプ受容体 / a1アドレナリン受容体 / Green Fluorecent Protein / 創薬ストラテジー / スプライスバリアント |
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| Research Abstract |
In the present study, we examined a new strategy for drug discovery based on the recent development in molecular biology. Recently, a number of G-protein coupled receptors (GPCR) have been cloned and are found to have a large gene family. Each GPCR has several subtypes and physiological function of the GPCR is mediated by these subtypes. We planed to clone all members of a certain GPCR in human by homology cloning method with PCR, and then construct cell lines stably expressing the cloned receptor, analyze the signal transduction, and as a final goal to discover a novel subtype receptor-specific drug by using the cells. Using alpha1-adrenoceptor (alpha1-AR) as a model, we examined this new strategy for drug discovery. We cloned three different human alpha1-AR subtypes (a, b and d-type), and obtained the cells stably expressing these three subtypes. All alpha1-AR s are found to be coupled to Gq/1 1 proteins and Ca2+ signaling. Utilizing these cell lines, we found that a novel alphal -AR antagonist KMD-3213 is very selective for alpha1 a-subtype, and can be very useful for the treatment of benign prostate hypertrophy without no untoward effect on the blood pressure. Furthermore, developing antibodies against alpha1 b-AR, we first succeeded in detecting the tissue localization of the alpha1 b-AR protein. Taken together, the present study clearly showed that molecular biological methodology can be potentially of use for drug discovery, targeted GPCR in particular.
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