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1995 Fiscal Year Final Research Report Summary

ESTABLISHMENT OF AN ANIMAL MODEL FOR CONGENITAL CRANIOFACIAL DISEASES BY GENE TARGETING AND DEVELOPMENT OF THEIR GENETIC DIAGNOSIS.

Research Project

Project/Area Number 06557065
Research Category

Grant-in-Aid for Developmental Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Embryonic/Neonatal medicine
Research InstitutionUniversity of Tokyo

Principal Investigator

KURIHARA Hiroki  University of Tokyo, Faculty of Medicine, ASSISTANT, 医学部(病), 助手 (20221947)

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)
Project Period (FY) 1994 – 1995
KeywordsEndothelin-1 / Gene-targeting / Knock-out mouse / Neural crest / Development / Congenital diseases / Polymorphism / Genetic diagnosis
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.

  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] 栗原由起子 他: "Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1." Nature. 368. 703-710 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 前村浩二 他: "Renal endothelin and hypertension-reply." Nature. 372. 50 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 栗原裕基 他: "Targeting gene expression to the vascular wall in transgenic mice using the murine preproendothlelin-1 gene." J.Clin.Invest.95. 1335-1344 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 栗原由起子 他: "Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1." J.Clin.Invest.96. 293-300 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 前村浩二 他: "Sequence analysis, chromosomal Jocation and developmental expression of the mouse preproendothelin-1 gene." Genomics. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 桑木共之 他: "Impaired ventilatory responses to hypoxia and hypercapnia in mutant mice deficient in endothelin-1." Am.J.Physiol.(in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Koji. MAEMURA et al.: "Isolation and characterization of vascular endothelial cells derived from nice lacking endcthelin-1." Biochem.Biophys.Res Commun.201. 538-545 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Toshisuke MORITA et al: "Role of Ca2+ and protein Uinase C in shear stress-induced actin depolymerization and endothelin-1 gene expression." Circ. Res. 75. 630-636 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yukiko. KURIHARA et al: "Role of endothelin in central cardiorespiratory control : modern and classical approaches." News in Physiol. Sci. 10. 228-233 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yukiko. KURIHARA et al: "Impaired development of the thyroid and thymus in endothelin-1 knockout mice." J. Cardiovasc. Pharmacol.26. S13-S16 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yukiko KURIHARA et al.: "Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1." Nature. 368. 703-710 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koji MAEMURA et al.: "Isolation and characterization of vascular endothelial cells derived from mice lacking endothelin-1." Biochem.Biophys.Res.Commun.201. 538-545 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hiroki KURIHARA et al.: "Targeting gene expression to the vascular wall in transgenic mice using the murine preproendothelin-1 promoter." J.Clin.Invest. 95. 1335-1344 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koji MAEMURA et al.: "Renal endothelin and hypertension - reply." Nature. 372. 50-50 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toshisuke MORITA et al.: "Role of Ca2+ and protein kinase C in shear stress-induced actin depolymerization and endothelin-1 gene expression." Circ.Res. 75. 630-636 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yukiko KURIHARA et al.: "Aortic arch malformations and ventricular septal defect in mice deficient in endothelin-1" J.Clin.Invest. 96. 293-300 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tomoyuki KUWAKI et al.: "Role of endothelin in central cardiorespiratory control : modern and classical approaches." News in Physiol.Sci.10. 228-233 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tomoyuki KUWAKI et al.: "Impaired vantilatory responses to hypoxia and hypercapnia in mutant mice deficient in endothelin-1" Am.J.Physiol. (in press). (1996)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yukiko KURIHARA et al.: "Impaired development of the thyroid and thymus in endothelin-1 knockout mice." J.Cardiovasc.Pharmacol. 26. S13-S16 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Koji MAEMURA et al.: "Sequence Analysis, Chromosomal Location and Developmental Expression of the Mouse Preproendothelin-1 Gene." Gene.Genomics. (in press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1997-03-04  

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