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

通过基因打靶建立先天性颅面疾病动物模型并开发其遗传诊断。

基本信息

批准号：
06557065
负责人：
KURIHARA Hiroki
金额：
$ 8.06万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

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.

在本研究中，我们已经阐明了新的发育作用的ET-1及其潜在的关联与人类颅面先天性疾病，通过建立ET-1基因敲除小鼠基因打靶和他们的分析。ET-1基因敲除小鼠不仅表现出颅面畸形，而且表现出相关的心血管异常（大血管畸形+室间隔缺损），这类似于人类先天性疾病，如CATCH 22和腭心面综合征。这些发现表明ET-1基因敲除小鼠可能是一种有用的疾病模型。我们推测ET-1可能作为神经嵴细胞发育中上皮-间质相互作用的介质，神经嵴细胞在咽弓和心血管系统的形成中起重要作用。我们还确定了ET-1通路下游的候选基因之一，包括ET-1在内的基因在咽弓和心血管发育中的相互作用将是我们未来研究的下一个主题。为了临床应用和新诊断方法的开发，我们发现了人ET-1基因外显子的多态性。通过使用这种多态性，我们现在正在研究ET-1基因与人类先天性疾病包括Pierre-Robin综合征，Treacher-Collins综合征和先天性心脏病之间的联系。此外，我们已经成功地建立了血管选择性基因表达系统使用ET-1基因启动子区和ET-1过表达小鼠使用该系统。对ET-1基因敲除小鼠和ET-1过表达小鼠的系统分析有望进一步阐明ET-1的病理生理作用。