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。

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06557065/
• 关键词: 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; 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

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，我们通过基因靶向及其分析来建立ET-1基因敲除小鼠，阐明了ET-1及其与人类颅面先天性疾病的潜在发展作用。 ET-1基因敲除小鼠不仅表现出颅面异常，而且还相关的心血管异常（巨大的血管畸形 +心室间隔缺陷），类似于人类先天性疾病，例如CATCEN22和VELO-Cardio-Facardio-Facial综合征。这些发现表明，ET-1敲除小鼠可能是有用的疾病模型。我们假设ET-1可以作为神经克雷斯特细胞发育中上皮 - 间质相互作用的介体，在咽弓和心血管系统的形成中起着重要作用。我们还确定了在ET-1途径下游的候选基因之一以及咽弓和心血管发育中包括ET-1在内的基因之间的相互作用将是我们未来研究的下一个主题之一。关于新诊断方法的临床意义和发展，我们发现了人类ET-1基因的外显子中的多态性。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（包括皮埃尔·罗宾综合症，背叛者 - 卷素综合征和先天性心脏病）之间的联系。此外，我们成功地使用ET-1基因启动子区域和ET-1过表达小鼠，成功地建立了血管选择性基因表达系统。对ET-1敲除小鼠和ET-1超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。