PHYSIOLOGICAL ROLE OF ADRENOMEDULLIN BY MOLECULAR BIOLOGICAL AND GENE ENGINEERING APPROACH

通过分子生物学和基因工程方法研究肾上腺髓质素的生理作用

• 批准号: 10218201
• 负责人: FUJITA Toshiro
• 金额: $ 35.39万
• 依托单位: UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10218201/
• 关键词: vasodilating agent; hypertension; insulin resistance; oxidative stress; knockout mice; organ damage; 心肥大; 血管障害; アドレノメデュリン; 高血圧; 血管平滑筋

Adrenomedullin and PAMP are derived from the same precursor protein and in order to clarify the physiological and therapeutical role of adrenomedullin, we generated adrenomedullin knockout mice by inserting stop mutation in the starting codon of adrenomedullin gene. The homozygous were embryonic lethal and we used heterozygotes. We have reported in 2001 that this mutant showed marked vascular damage by angiotensin II possibly through, overproduction of oxidative stress. In 2002, we demonstrated that aged mutants accumulate oxidative stress and insulin resistance was observed in this aged mutant. Adrenomedullin supplementation or treatment with super oxide dismutase successfully reversed insulin resistant state in the mutants. These results suggest that adrenomedullin is an intrinsic anti-oxidant and its deficiency will cause several oragan damages. Moreover, it will he a new therapeutical agent to prevent complications in common disease such as hypertension, diabetes.

肾上腺髓质素和PAMP来源于相同的前体蛋白，为了阐明肾上腺髓质素的生理和治疗作用，我们通过在肾上腺髓质素基因的起始密码子插入终止突变来产生肾上腺髓质素敲除小鼠。纯合子是胚胎致死的，我们使用杂合子。我们在2001年曾报道，这种突变体显示血管紧张素II可能通过过度产生氧化应激引起显著的血管损伤。在2002年，我们证明了老年突变体积累氧化应激和胰岛素抵抗，观察到在这个老年突变体。补充肾上腺髓质素或用超氧化物歧化酶治疗成功地逆转了突变体的胰岛素抵抗状态。这些结果表明，肾上腺髓质素是一种内在的抗氧化剂，它的缺乏将导致多种oragan损害。此外，它还将成为预防高血压、糖尿病等常见疾病并发症的新的治疗药物。

项目成果

Takano K, et al.: "Proadrenomedullin N-terminal 20 peptide hyperpolarizes the membrane by activating an inwardly rectifying K+ current in differentiated PC12 cells"Circ Res.. 84(4). 445-450 (1999)

Takano K 等人：“前肾髓质素 N 端 20 肽通过激活分化的 PC12 细胞中的内向整流 K 电流使膜超极化”Circ Res.. 84(4)。

Tajima A, et al.: "Distribution of adrenomedullin (AM), proadrenomedullin N-terminal 20 peptide, and AM mRNA in the rat gastric mucosa by immunocytochemistry and in situ hybridization"Histochem Cell Biol. 112(2). 139-146 (1999)

Tajima A 等人：“通过免疫细胞化学和原位杂交测定大鼠胃粘膜中肾上腺髓质素 (AM)、肾上腺髓质素原 N 端 20 肽和 AM mRNA 的分布”Histochem Cell Biol。

Shimosawa T, et al.: "Adrenomedullin, an Endogenous Peptide, Counteracts Cardiovascular Damage"Circulation. 105. 106-111 (2002)

Shimosawa T 等人：“肾上腺髓质素，一种内源性肽，可抵抗心血管损伤”循环。

Takano K, et al.: "Proddrenomedullin Nterminal 20 peptide hyporpolarzes the membrane by activaty" Circulation Research. 84 (4). 445-50 (1999)

Takano K 等人：“Proddrenomedullin N 末端 20 肽通过激活使膜低极化”循环研究。

Hayashi M, et al.: "Hyperglycemia increases vascular adrenomedullin expression"Biochem Biophys Res Commun. 258(2). 453-456 (1999)

Hayashi M 等人：“高血糖增加血管肾上腺髓质素表达”Biochem Biophys Res Commun。