| Project/Area Number |
06557065
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Embryonic/Neonatal medicine
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| Research Institution | University of Tokyo |
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Principal Investigator |
KURIHARA Hiroki University of Tokyo, Faculty of Medicine, ASSISTANT, 医学部(病), 助手 (20221947)
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| Co-Investigator(Kenkyū-buntansha) |
MAEMURA Koji University of Tokyo, Faculty of Medicine, ASSISTANT, 医学部(病), 医員
KODAMA Tatsuhiko University of Tokyo, Faculty of Medicine, ASSISTANT, 医学部(病), 助手 (90170266)
KAGA Kimitaka University of Tokyo, Faculty of Medicine, PROFESSOR, 医学部(病), 教授 (80082238)
ISHIKAWA Takatoshi University of Tokyo, Faculty of Medicine, PROFESSOR, 医学部(医), 教授 (30085633)
YAZAKI Yoshio University of Tokyo, Faculty of Medicine, PROFESSOR, 医学部(病), 教授 (20101090)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥12,600,000 (Direct Cost: ¥12,600,000)
Fiscal Year 1995: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 1994: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | Endothelin-1 / Gene-targeting / Knock-out mouse / Neural crest / Development / Congenital diseases / Polymorphism / Genetic diagnosis / ジ-ソターゲティング / 神経提細胞 / ジーンターダティング / エンドセリン / 血圧調節 / 胎児発達 / 遺伝子診断 / モデル動物 |
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| Research Abstract |
In the present study, we have clarified the novel developmental role of ET-1 and its potential association with human craniofacial congenital diseases through the establishment of ET-1 knockout mice by gene targeting and their analysis. ET-1 knockout mice demonstrated not only craniofacial abnormalities but also associated cardiovascular anomalies (great vessel malformations + ventricular septal defect), which resemble human congenital diseases such as CATCH22 and velo-cardio-facial syndrome. These findings suggest that ET-1 knockout mice may be a useful disease model. We hypothesized that ET-1 may serve as mediator of the epithelial-mesenchymal interaction in the development of neural crest cells which plays an important role in the formation of the pharyngeal arches and cardiovascular system. We have also identified one of the candidate genes downstream to the ET-1 pathway and interaction among genes including ET-1 in the pharyngeal arch and cardiovascular development will be one of the next theme of our future research. Concerning the clinical implication and development of new diagnostic methods, we have found a polymorphism in the exon of the human ET-1 gene. By using this polymorphism, we are now examining the linkage between the ET-1 gene and human congenital diseases including Pierre-Robin syndrome, Treacher-Collins syndrome and congenital heart diseases. Furthermore, we have succeeded in establishing the vessel-selective gene expression system using the ET-1 gene promoter region and ET-1 overexpressing mice using this system. Systematic analysis of both ET-1 knockout mice and ET-1-overexpression mice is expected to further elucidate the pathophysiological role of ET-1.
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