Development of murine models of disease using a novel non-obese type 2 diabetes mellitus mouse discovered in Japan and isolation of responsible genes

The murine models of diabetes reported in the present study are novel models of spontaneous disease. The mice are non-obese and show autosomal dominant inheritance. The type 2 diabetes models are heterozygote strains, whereas the neonatal diabetes mellitus models are homozygote strains that die due to severe hyperglycemia at 4 days after birth. The progenitor mutant mouse was discovered in the F2 population between the two inbred mouse strains NC/Jic and KOR1. Because diabetes is a multifactorial disease and its genetic analysis is difficult, murine models with the same genetic background were developed to isolate modification genes responsible for the onset of diabetes. Hybridization was used to introduce the mutant genes into 10 inbred strains with different genetic backgrounds to create congenic murine models of diabetes and into four apoE-deficient hyperlipidemia mouse (SHL) strains to develop murine models of diabetes with hyperlipidemia. Development of 機関番号：82402 研究種目：基盤研究(B) 研究期 … More 間：2009年度～2012年度 課題番号：21300156 研究課題名（和文） 我国で発見された新規非肥２型糖尿病マウスによる疾患モデル群樹立と原因遺伝子の特定 研究課題名（英文） Development of murine models of disease using a novel non-obese type 2 diabetes mellitus mouse discovered in Japan and isolation of responsible genes 研究代表者 松 島 芳 文 （マツシマ ヨシブミ） 研究者番号：10094955 congenic murine models is completed at the N12 or a later generation. Eight congenic strains for diabetes (AKR, BALB/c, C3H/He, C57BL/6, DBA/2, JF1, NC/Jic, and NC/Nga) and four strains for diabetes with hyperlipidemia (B6.SHL, C.SHL, C3.SHL, and D2.SHL) have been successfully developed in this study. However, A/J and KORI are both at the N6 generation and are being advanced to the later generations to generate congenic strains. These congenic strains showed prominent differences with respect to various phenotypic characteristics, such as age in weeks at urinary sugar manifestation, blood sugar level, and sex difference, at disease onset. Therefore, they also have utility as novel models for personalized medicine. There are, as yet, few reports on the development of diabetic nephropathy models that researchers long for. However, pathological observations of the kidneys of the C57BL/6 congenic strain suggest that it may be a novel model of diabetic nephropathy. Positional cloning of the responsible gene has narrowed down the candidate region to the vicinity of the centromere of the mouse chromosome 8. DNA sequencing is ongoing, and the results there of will be available before manuscript submission. Less

The murine models of diabetes reported in the present study are novel models of spontaneous disease. The mice are non-obese and show autosomal dominant inheritance. The type 2 diabetes models are heterozygote strains, whereas the neonatal diabetes mellitus models are homozygote strains that die due to severe hyperglycemia at 4 days after birth. The progenitor mutant mouse was discovered in the F2 population between the two inbred mouse strains NC/Jic and KOR1. Because diabetes is a multifactorial disease and its genetic analysis is difficult, murine models with the same genetic background were developed to isolate modification genes responsible for the onset of diabetes. Hybridization was used to introduce the mutant genes into 10 inbred strains with different genetic backgrounds to create congenic murine models of diabetes and into four apoE-deficient hyperlipidemia mouse (SHL) strains to develop murine models of diabetes with hyperlipidemia. Development of 機関番号：82402 研究種目：基盤研究(B) 研究期 … More 間：2009年度～2012年度 課題番号：21300156 研究課題名（和文） 我国で発見された新規非肥２型糖尿病マウスによる疾患モデル群樹立と原因遺伝子の特定 研究課題名（英文） Development of murine models of disease using a novel non-obese type 2 diabetes mellitus mouse discovered in Japan and isolation of responsible genes 研究代表者 松 島 芳 文 （マツシマ ヨシブミ） 研究者番号：10094955 congenic murine models is completed at the N12 or a later generation. Eight congenic strains for diabetes (AKR, BALB/c, C3H/He, C57BL/6, DBA/2, JF1, NC/Jic, and NC/Nga) and four strains for diabetes with hyperlipidemia (B6.SHL, C.SHL, C3.SHL, and D2.SHL) have been successfully developed in this study. However, A/J and KORI are both at the N6 generation and are being advanced to the later generations to generate congenic strains. These congenic strains showed prominent differences with respect to various phenotypic characteristics, such as age in weeks at urinary sugar manifestation, blood sugar level, and sex difference, at disease onset. Therefore, they also have utility as novel models for personalized medicine. There are, as yet, few reports on the development of diabetic nephropathy models that researchers long for. However, pathological observations of the kidneys of the C57BL/6 congenic strain suggest that it may be a novel model of diabetic nephropathy. Positional cloning of the responsible gene has narrowed down the candidate region to the vicinity of the centromere of the mouse chromosome 8. DNA sequencing is ongoing, and the results there of will be available before manuscript submission. Less