Genetic analysis of the molecular basis of insulin resistance both in animal models and in humans.

对动物模型和人类胰岛素抵抗的分子基础进行遗传分析。

• 批准号: 12470226
• 负责人: GOTODA Takanari
• 金额: $ 7.36万
• 依托单位: Tokyo Woman's Medical University (2001)The University of Tokyo (2000)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470226/
• 关键词: Insulin resistance; Animal model; Gene; QTL; Chromosome 9; SHR; QTL解析; ラット; 高血圧; キヌレニン

SHR is a genetic model of human insulin resistance syndrome (IRS). Quantitative trait loci (QTLs) for IRS-related phenotypes have been mapped to the regions on rat chromosomes (Chrs) 3, 4 and 12. Interestingly, multiple QILs have been shown to cluster around a single region on either Chr 3 or 4. In SHR strains derived from the NIH, USA, a deletional mutation has been identified in the Cd36 located within the Chr 4-QTL region. The mutation was, however, absent in the Cd36 of the original SHR strains and was shown to be introduced during breeding at the NIH. Comparison between SHR strains indicated that the Cd36 mutation is unlikely to be a major cause of insulin resistance phenotypes in SHR. QTLs for hypertension, reduced adiposity and insulin resistance in SHR, as well as a candidate gene (KAT-1) locus, have been mapped to an overlapping region of the proximal end of rat Chr 3. We have identified a functional missense mutation in the KAT-1 derived from all SHR strains examined. The chromosomal localization of the human homologue of KAT-1 to human Chr 9q22, where diabetes, hypertension and obesity have previously been linked, warrants further investigation of the homologue of KAT-i in humans.

SHR是人类胰岛素抵抗综合征(IRS)的遗传模型。IRS相关表型的数量性状基因座(QTL)已被定位于大鼠染色体(CHR)3、4和12上的区域。有趣的是，已发现多个QIL聚集在Chr 3或Chr 4上的单个区域。在来自美国国家卫生研究院的SHR株中，位于Chr 4-QTL区域的CD36被发现存在缺失突变。然而，在最初的SHR菌株的CD36中没有这种突变，并被证明是在NIH的育种过程中引入的。不同SHR株之间的比较表明，CD36突变不太可能是SHR胰岛素抵抗表型的主要原因。SHR高血压、肥胖减少和胰岛素抵抗的QTL以及候选基因(Kat-1)已被定位到大鼠Chr3近端的重叠区域。我们在所有被检测的SHR株Kat-1中发现了一个功能性错义突变。人类Kat-1与人类Chr 9q22的同源物的染色体定位，以前曾与糖尿病、高血压和肥胖症联系在一起，需要进一步研究Kat-I在人类中的同源物。

项目成果

T Yoshida, T Gotoda, M Okubo, Y Iizuka, S Ishibashi, T Kojima, T Murakami, T Murase, N Yamada.: "A Japanese patient with lipoprotein lipase deficiency homozygous for the Gly188Glu mutation prevalent worldwide"J Arterioscler Thromb. 7. 45-49 (2000)

T Yoshida、T Gotoda、M Okubo、Y Iizuka、S Ishibashi、T Kojima、T Murakami、T Murase、N Yamada.：“一名患有脂蛋白脂肪酶缺乏症的日本患者，其 Gly188Glu 突变纯合于世界各地”J Arterioscler Thromb。

H Yagyu, T Kitamine, J Osuga, R Tozawa, Z Chen, Y Kaji, T Oka, S Perrey, Y Tamura, K Ohashi, H Okazaki, N Yahagi, F Shionoiri, Y Iizuka, K Hamada, H Shimano, H Yamashita, T Gotoda, N Yamada, S Ishibashi.: "Absence of ACAT-1 attenuates atherosclerosis but

H 柳生、T Kitamine、J Osuga、R Tozawa、Z Chen、Y Kaji、T Oka、S Perrey、Y Tamura、K Ohashi、H 冈崎、N Yahagi、F Shionoiri、Y Iizuka、K Hamada、H Shimano、H Yamashita

AH Hasty, H Shimano, JI Osuga, I Namatane, A Takahashi, N Yahagi, S Pettey, Y Iizuka, Y Tamura, M Amemiya-Kudo, T Yoshikawa, H Okazaki, K Ohashi, K Harada, T Matsuzaka, H Sone, T Gotoda, R Nagai, S Ishibashi, N Yamada.: "Severe hypercholesterolemia, hyper

AH Hasty、H Shimano、JI Osuga、I Namatane、A Takahashi、N Yahagi、S Pettey、Y Iizuka、Y Tamura、M Amemiya-Kudo、T Yoshikawa、H Okazaki、K Ohashi、K Harada、T Matsuzaka、H Sone、

N Kato, T Tamada, T Nabika, K Ueno, T Gotoda, C Matsumoto, T Mashimo, K Ikeda, Y Nara, Y Yamori.: "Identifications of quantitative trait loct for serum cholesterol levels in Stroke-prone Spontaneously Hypertensive Rats."Arterioscler Thromb Vasc Boil. 20.

N Kato、T Tamada、T Nabika、K Ueno、T Gotoda、C Matsumoto、T Mashimo、K Ikeda、Y Nara、Y Yamori.：“易中风自发性高血压大鼠血清胆固醇水平数量性状基因组的鉴定。”

Hasty AH, Shimano H, Gotoda T, et al.: "Severe hypercholesterolemia, hyperinglyceridemia, and atherosderosis in mice lacking both leptin and the low density lipoprotein receptor"J. Biol. Chem.. 276・40. 37402-37408 (2001)

Hasty AH、Shimano H、Gotoda T 等：“缺乏瘦素和低密度脂蛋白受体的小鼠中的严重高胆固醇血症、高甘油酯血症和动脉粥样硬化” J. Biol Chem. 276・40 (2001)。