| Project/Area Number |
12480249
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory animal science
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| Research Institution | Institute for Molecular and Cellular Regulation, Gunma University |
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Principal Investigator |
IZUMI Tetsuro Gunma University, Department of Molecular Medicine, Institute forMolecular and Cellular Regulation, Professor,, 生体調節研究所, 教授 (00212952)
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| Co-Investigator(Kenkyū-buntansha) |
為本 浩至 自治医科大学, 大宮医療センター, 講師 (90292630)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥5,600,000 (Direct Cost: ¥5,600,000)
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| Keywords | diabetes / rodent models / quantitative trait locus / insulin secretion / pancreatic beta cells / 肥満 |
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| Research Abstract |
We have investigated the molecular pathogenesis of diabetes using rodent disease models.
(1) TSOD mouse
We previously performed genetic analysis of diabetes and obesity in TSOD mice and identified three quantitative trait loci (QTLs). Our final goal is to identify genetic alterations at each QTL. For this-purpose, we have generated several congenic strains. For example, 17 congenic strains were constructed for the QTL on chromosome 2 that influences the body weight and plasma insulin levels of TSOD mice. By comparing phenotypes between the congenic strains and parental TSOD mice, the QTL regions can be narrowed down. In case of the QTL on chromosome 2, we can successfully define it to a 12.8-Mb region that contains 49 candidate genes.
(2) Akita mouse
We previously discovered that autosomal dominant diabetes in the Akita mouse is caused by mutation of, the insulin 2 gene, whose product replaces a cysteine residue that is engaged in the formation of an intramolecular disulfide bond. The heterozygous mice exhibit severe insulin deficiency despite coexpression of normal insulin molecules derived from three other wild-type alleles of the insulin 1 and 2 genes. We investigated the dominant-negative pathogenic mechanisms induced by the mutant proinsulin 2, and found that the trafficking of constitutively secreted alkaline phosphatase is significantly decreased in the islets of Akita mice. Morphologic analysis also revealed that secretory pathway organelle architecture is progressively devastated in the β-cells of Akita mice. These findings suggest that the organelle dysfunction due to the intracellular accumulation of misfolded proinsulin 2 is primarily responsible for the defect of coexisting wild-type insulin secretion in Akita β-cells.
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