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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敲除和CNP转基因小鼠的产生和分析：为了研究CNP在体内的生理意义，我们产生了靶向破坏CNP的小鼠（CNP^<-1->小鼠）。CNP^<-1->小鼠由于软骨内成骨受损而表现出严重的侏儒症。它们都能在围产期存活，但只有不到一半能在产后发育期间存活。骨骼表型在组织学上与软骨发育不全患者相似，软骨发育不全是人类侏儒症最常见的遗传形式。生长板软骨细胞靶向表达CNP可修复CNP^<-1->小鼠骨骼缺损，延长其生存期。本研究表明，CNP在体内作为软骨内成骨的局部积极调节因子，并提示其在某些形式的骨骼发育不良中的病理生理和治疗意义。BNP转基因小鼠和GC-A基因敲除小鼠之间的遗传杂交：BNP是一种主要由心室产生的激素，被认为通过其同源受体，guanyyl环化酶a （GC-A）参与多种稳态过程。为了确定BNP是否仅通过GC-A发挥其生物学作用，我们制造了缺乏GC-A的BNP转基因小鼠（BNP- tg /GC-A^<-1->小鼠），并检测了它们的心血管和骨骼表型。与野生型小鼠相比，GC-A^<-1->小鼠出现高血压并伴有心肌肥厚，而BNP在BNP- tg /GC-A^<-1->小鼠中的过度表达并未减轻这种情况。然而，与BNP-Tg小鼠相比，BNP-Tg/GC-A^<-1->小鼠继续表现出明显的椎骨和长骨纵向生长。这项研究提供了遗传证据，证明BNP通过GC-A降低血压和心脏重量，而在缺乏这种受体的情况下，它会显著改变软骨内成骨。因此，BNP-Tg/GC-A^<-1->小鼠提供了第一个实验模型，证明该利钠肽可以通过GC-A以外的受体以组织特异性的方式发出信号。少