Study of New Roles in AMP Metabolism by Using Gene Modified Animals

利用基因修饰动物研究 AMP 代谢中的新作用

• 批准号: 16590259
• 负责人: MORISAKI Takayuki
• 金额: $ 2.24万
• 依托单位: National Cardiovascular Center Research Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590259/
• 关键词: nucleotide metabolism; AMP deaminase; metabolic disorder; myopathy; disease model; gene modified animal; AMP; モデル動物; 遺伝子破壊

AMP deaminase (AMPD) catalyzes AMP to IMP and is thought to play an important role in purine metabolism, though detailed function of AMPD in vivo has not been understood. Therefore, we established gene knock-out mice for each AMPD gene to elucidate in vivo function of three AMPD genes. Furthermore, we tried to produce model mice for combined AMPD deficiency by mating these AMPD knock-out mice. AMPD2 knockout mice showed muscle specific deficiency of AMPD and increased AMP/ATP ratio in skeletal muscle as well as more phophorylation of AMP-activated kinase in muscle. AMPD2 knockout mice exhibited proteinuria along with decreased AMPD activity in kidney and liver. Also, they showed increased AMP and increase of phophorylated AMPK and ACC in liver. AMPD3 knockout mice exhibited decreased AMPD acitivity in red cells and heart, and they showed increased ATP in red cells without other prominent phenotype. About combined AMPD deficiency, AMPD2/AMPD3 double deficient mice were found to die before 3 weeks after birth, though AMPD1/AMPD2 double deficient mice as well as AMPD1/AMPD3 double deficient mice were established. These studies revealed the functional relevance of AMPD in kidney as well as liver.

AMP脱氨酶(AMPD)催化AMP转化为IMP，被认为在嘌呤代谢中起重要作用，但AMPD在体内的具体功能尚不清楚。因此，我们建立了针对每个AMPD基因的基因敲除小鼠，以阐明三个AMPD基因在体内的功能。此外，我们试图通过交配这些AMPD基因敲除的小鼠来制造AMPD联合缺乏症的模型小鼠。AMPD2基因敲除小鼠表现出肌肉特异性AMPD缺乏，骨骼肌AMP/ATP比值增加，肌肉中AMP激活的激酶磷酸化程度增加。AMPD2基因敲除小鼠出现蛋白尿，肾脏和肝脏AMPD活性降低。肝组织中AMP升高，磷酸化AMPK和ACC升高。AMPD3基因敲除小鼠的红细胞和心脏中的AMPD活性降低，红细胞中的ATP活性升高，但没有其他明显的表型。在AMPD复合缺陷方面，虽然建立了AMPD1/AMPD2双缺陷小鼠和AMPD1/AMPD3双缺陷小鼠，但发现AMPD2/AMPD3双缺陷小鼠在出生后3周内死亡。这些研究揭示了AMPD在肾脏和肝脏中的功能相关性。

项目成果

高尿酸血症と痛風 : AMPデアミナーゼと循環器疾患

高尿酸血症和痛风：AMP 脱氨酶和心血管疾病

• 发表时间: 2005
• 作者: Sugiura;H. et al.;森崎隆幸
• 通讯作者: 森崎隆幸

高尿酸血症と通風:AMPデアミナーゼと循環器疾患

高尿酸血症和痛风：AMP 脱氨酶和心血管疾病

• 发表时间: 2005
• 作者: Ihara;S;N.Koshikawa;森崎 隆幸
• 通讯作者: 森崎 隆幸

Stable and uniform gene suppression by site-specific integration of siRNA expression cassette in murine embryonic stem cells.

通过将 siRNA 表达盒定点整合到小鼠胚胎干细胞中，实现稳定且一致的基因抑制。

• 发表时间: 2005
• 期刊: Stem Cells 23(8)
• 作者: Zheng GD;Hidaka K;Morisaki T
• 通讯作者: Morisaki T

Haplotype analysis of human AMPD1 gene. Origin of common mutant allele

人类 AMPD1 基因的单倍型分析。

• 发表时间: 2004
• 期刊: Journal of Medical Genetics 41
• 作者: Kurahashi H;Taniguchi M;Meno C;Taniguchi Y;Takeda S;et al.;K.Furukawa et al.;Toyama K et al.
• 通讯作者: Toyama K et al.