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Novel methods to avoid difficulties from juvenile lethality or growth retardation in knockout mice and to study circulatory, respiratory, and autonomic functions in them

避免基因敲除小鼠幼年致死或生长迟缓困难并研究其循环、呼吸和自主功能的新方法

基本信息

批准号：
08457008
负责人：
KUWAKI Tomoyuki
金额：
$ 3.46万
依托单位：
Chiba University (1997)The University of Tokyo (1996)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

Five methods were developed to avoid difficulties from juvenile lethality or growth retardation in knockout mice and to study circulatory, respiratory, and autonomic functions in them : to make medulla-spinal cord preparation from newborn mice, a way to rescue newborn pups with tracheotomy, special small devices to measure blood pressure and respiratory mechanics, construction of artificial anus, and genetic rescue. These methods were applied to endothelin (ET) -1 knockout mouse, ET-A receptor (ETAR) knockout mouse, ET-B receptor (ETBR) knockout mouse, and insulin receptor substrate-1 (IRS-1) knockout mouse. Medulla-spinal cord preparation from ET-1 knockout mice and tracheotomized newborn mice of ET-1 knockout and ETAR knockout showed severe attenuation of respiratory reflex to hypercapnia. Endogenous ET-1-ETAR system thus physiologically participates in the central chemosensitivity. In genetically established mutant mice in which ETBR was 1/8 of normal mice, arterial blood pressure (AP) was elevated with normal sympathetic activity and respiration. The result is consistent with a pressor response to selective blockade of ETBR in normal mice. Thus, ETBR contribute physiologically to diminish basal level of AP through peripheral mechanism. IRS-1 knockout mice showed growth retardation and elevation of AP.Thus IRS-1 is also essential to maintain normal AP.In conclusion, knockout mice are a valuable research resource especially in the study of integrative physiological functions of mammals.

为避免基因敲除小鼠幼崽死亡或生长迟缓的困难，研究其循环、呼吸和自主神经功能，提出了5种方法：从新生小鼠身上制备髓脊髓，用气管切开术抢救新生幼鼠，用特殊的小型装置测量血压和呼吸力学，构建人工肛门和基因抢救。这些方法分别应用于内皮素(ET) -1敲除小鼠、ET- a受体（ETAR）敲除小鼠、ET- b受体（ETBR）敲除小鼠和胰岛素受体底物-1 （IRS-1）敲除小鼠。从ET-1基因敲除小鼠和气管切除的ET-1基因敲除和ETAR基因敲除的新生小鼠的髓脊髓制备中发现，呼吸反射对高碳酸血症的严重衰减。因此，内源性ET-1-ETAR系统在生理上参与中枢化学敏感性。在ETBR为正常小鼠1/8的基因突变小鼠中，动脉血压（AP）升高，交感神经活动和呼吸正常。结果与正常小鼠选择性阻断ETBR的压力反应一致。因此，ETBR在生理上通过外周机制降低AP基础水平。IRS-1基因敲除小鼠表现出生长迟缓和ap升高，因此IRS-1基因敲除小鼠对维持正常ap也是必不可少的。因此，IRS-1基因敲除小鼠是研究哺乳动物综合生理功能的宝贵研究资源。