| Project/Area Number |
12204007
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Ehime University |
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Principal Investigator |
HIDEICHI Hideichi Ehime University School of Medicine, Department of Laboratory Medicine, Professor, 医学部, 教授 (50009578)
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| Co-Investigator(Kenkyū-buntansha) |
OOSAWA Haruhiko Ehime University School of Medicine, Dpartment of Laboratory Medicine, Associate Professor, 医学部, 助教授 (90294800)
ONUNA Hiroshi Ehime University School of Medicine, Department of Laboratory Medicine, Assistant Professor, 医学部, 助手 (00294794)
橋本 尚武 千葉大学, 医学部, 助教授 (00272328)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥47,100,000 (Direct Cost: ¥47,100,000)
Fiscal Year 2004: ¥9,600,000 (Direct Cost: ¥9,600,000)
Fiscal Year 2003: ¥11,500,000 (Direct Cost: ¥11,500,000)
Fiscal Year 2002: ¥12,000,000 (Direct Cost: ¥12,000,000)
Fiscal Year 2001: ¥14,000,000 (Direct Cost: ¥14,000,000)
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| Keywords | diabetes / susceptibility genes / SNP / polymorphism / insulin resistance / adipocytokine / resistin / transcription / 転写因子 / ハプロタイプ / PDE3B / 脂肪細胞 / インスリン / 遺伝子 / 疾患感受性 / PDE |
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| Research Abstract |
To identify diabetes susceptibility genes in Japanese, 1) we analyzed the association of single nucleotide polymorphisms (SNPs) and haplotypes of candidate genes with diabetes, 2) we examined factors regulating phosphodiesterase 3B (PDE3B), a promising candidate gene for insulin resistance seen with type 2 debates. In type 1 diabetes, we conducted a clinical study called "Ehime Study" where we screened a large number of diabetic subjects using glutamic acid decarboxylase antibody, a marker for self-immune-mediated diabetes. We classified GAD positive subjects into insulin-deficient and non-insulin-deficient groups, and elucidated characteristics of adult type 1 diabetes. In type 2 diabetes, we analyzed SNPs of candidate genes such as insulin, insulin receptor, and FOXC2 using cases and controls, but no significant association was evident. Then, we focused on resistin, a cytokine inducing insulin resistance. Its promoter SNP at-420 was found to be a type 2 diabetes susceptibility gene. The G/G genotype was associated with type 2 diabetes with odds ratio about two. In functional analysis, Sp1/3 transcription factors specifically recognized G at-420, and enhanced the resistin promoter activity. In humans, serum and monocyte mRNA levels of resistin was highest in the G/G genotype, followed by C/G, and C/C. In terms of adipocyte PDE3B, its gene expression was reduced in obese insulin-resistant mice. PDE3B gene expression was positively regulated by peroxisome proliferator-activated receptor γ (PPARγ) and adipocyte differentiation, and negatively regulated by adipocyte size in vitro. We also identified 14-3-3 protein as an interacting factor with PDE3B. We also cloned PDE3B gene promoter, and analyzed its SNPs but they were not associated with type 2 diabetes.
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