Physiologic and pathophysiologic role of C-type natriuretic peptide

C型利钠肽的生理和病理生理作用

基本信息

批准号：
11470226
负责人：
OGAWA Yoshihiro
金额：
$ 9.15万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

1.Generation and Analysis of CNP-knockout and CNP-transgenic mice :To investigate the physiological significance of CNP in vivo, we generated mice with targeted disruption of CNP (CNP^<-1-> mice). The CNP^<-1-> mice show severe dwarfism as a result of impaired endochondral ossification. They are all viable perinatally, but less than half can survive during postnatal development. The skeletal phenotypes are histologically similar to those seen in patients with achondroplasia, the most common genetic form of human dwarfism. Targeted expression of CNP in the growth plate chondrocytes can rescue the skeletal defect of CNP^<-1-> mice and allow their prolonged survival. This study demonstrates that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggests its pathophysiological and therapeutic implication in some forms of skeletal dysplasia.2.Genetic cross between BNP-transgenic and GC-A knockout mice :BNP, a hormone produced primarily by the cardiac ventricl … More e, is thought to be involved in a variety of homeostatic processes through its cognate receptor, guanylyl cyclase A (GC-A). To address whether BNP exerts its biological effects solely through GC-A, we produced BNP-transgenic mice lacking GC-A (BNP-Tg/GC-A^<-1-> mice) and examined their cardiovascular and skeletal phenotypes. The GC-A^<-1-> mice are hypertensive with cardiac hypertrophy relative to wild-type littermates, which is not alleviated by overexpression of BNP in BNP-Tg/GC-A^<-1-> mice. The BNP-Tg/GC-A^<-1-> mice, however, continue to exhibit marked longitudinal growth of vertebrae and long bones comparably to BNP-Tg mice. This study provides genetic evidence that BNP reduces blood pressure and cardiac weight through GC-A, whereas it dramatically alters endochondral ossification in the absence of this receptor. Therefore, the BNP-Tg/GC-A^<-1-> mice provide the first experimental model demonstrating that this natriuretic peptide can signal in a tissue-specific manner through a receptor other than GC-A. Less

1. CNP-KNOCKOUT ANP - 转基因小鼠的世代和分析：CNP在体内的生理意义，靶向CNP的破坏（CNP^<-1->小鼠）。骨骼的骨骼发育切断。在体内作为阳性调节剂的阳性骨化骨化，并在某些形式的骨骼发育异常中提出其病理生理和治疗性。2。BNP-转基因GC-A T小鼠之间的遗传杂交：BNP：BNP，一种基于心脏的激素……更多的荷尔蒙……更多的心脏。，通过其同源受体GC-A参与各种稳态过程，我们生产了缺少GC-A（BNP-TG/GC-A^-1->小鼠）的BNP-转基因小鼠并检查了心血管张口和骨骼表型。 BNP-TG/GC-A^<-1->继续表现出明显的纵向生长，而长骨则提供了遗传证据BNP-TG/GC-A^<-1->小鼠提供了第一个实验模型，表明该纳地尿肽可以通过除GC-A以外的其他方式以组织特异性的方式发出信号