ESTABLISHMENT OF MICE DEFICTENT IN A VASOACTIVE PEPTIDE BY GENE TARGETING AND THEIR APPLICATION TO PATHOPHYSIOLOGICAL ANALYSIS

通过基因打靶建立血管活性肽缺陷小鼠及其在病理生理学分析中的应用

基本信息

批准号：
06454286
负责人：
KURIHARA Hiroki
金额：
$ 4.54万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General 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 and the implication in blood pressure regulation of ET-1 through the establishment of ET-1-knockout mice by gene targeting and their analysis. We hypothesized that ET-1 may serve as a 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. Particularly, the phenotype of ET-1 knockout homozyotes (craniofacial abnormalities+great vessel malformations+ventricular septal defect) and human congenital diseases such as CATCH22 and velo-cardio-facial syndrome are very similar, suggesting that ET-1 knockout mice may give a clue to clarification of the genetic mechanism of these diseases and development of new therapeutic strategis. In ET-1 knockout heterozygotes, blood pressure was paradoxically elevated, indicating that ET-1 may not simply act as a pressor and the involvement of ET-1 in the regulation of cardiovascular homeostasis is rather complicated. Subsequently, we have found abnormalities in respiration and response to stress in addition to blood pressure elevation in ET-1 knockout mice. These findings have shed a light on the role of ET-1 in central cardiopulmonary regulation. In the elucidation of the pathophysiological role of ET-1, it would be of great use to make disease models inET-1 knockout mice. Establishment of disease models including atherosclerosis and hypertension in ET-1 knockout mice is in progress. 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 pahophysiological role of ET-1.

在本研究中，我们通过通过基因靶向及其分析来建立ET-1-敲除小鼠来阐明了新的发育作用以及对ET-1的血压调节的影响。我们假设ET-1可以作为神经骨细胞发展中上皮 - 间质相互作用的介体，在神经座细胞的发展中，在咽弓和心血管系统的形成中起着重要作用。特别是，ET-1基因敲除纯合的表型（颅面异常+出色的血管畸形+心室间隔缺陷）和人类先天性疾病（例如Catch22和Velo-Cardio-Facial综合征线索阐明这些疾病的遗传机制和新的治疗策略的发展。在ET-1基因敲除杂合子中，血压矛盾地升高，表明ET-1不仅可以充当压力，而且ET-1参与心血管稳态的调节很复杂。随后，除了ET-1基因敲除小鼠的血压升高外，我们发现呼吸和压力的反应异常。这些发现阐明了ET-1在中央心肺调节中的作用。在阐明ET-1的病理生理作用时，使疾病模型INET-1敲除小鼠非常有用。在ET-1敲除小鼠中建立包括动脉粥样硬化和高血压在内的疾病模型正在进行中。此外，我们成功地使用ET-1基因启动子区域和使用该系统过表达ET-1的小鼠建立了血管选择性基因表达系统。 ET-1基因敲除小鼠和ET-1过表达小鼠的系统分析预计将进一步阐明ET-1的Pahophosiology作用。