| Project/Area Number |
13557091
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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 | 展開研究 |
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| Research Field |
Metabolomics
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| Research Institution | GUNMA UNIVERSITY |
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Principal Investigator |
HORIKAWA Yukio Gunma University, Inst.Mol.Cell.Reg., Associate Professor, 生体調節研究所, 助教授 (10323370)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEDA Jun Gunma University, Inst.Mol.Cell.Reg., Professor, 生体調節研究所, 教授 (40270855)
正 公枝 群馬大学, 生体調節研究所, 教務員 (40201561)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥11,800,000 (Direct Cost: ¥11,800,000)
Fiscal Year 2003: ¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2002: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2001: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | type 2 diabetes / calpain-10 / transgenic mice / knockout mice / カルパイン3 / 疾患感受性多型 |
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| Research Abstract |
Multiple genetic and environmental factors cooperate to develop polygenic disease like type2 diabetes. The first identified susceptibility gene to type 2 diabetes, i.e.calpain 10, increases the risk of the disease in concert with the NIDDM3 gene located at chromosome 15. As the calpain 3 gene is located in the susceptibility gene locus NIDDM3, we planned to generate transgenic mice overexpressing either human calpain 10 or calpain 3 in pancreatic β cells and skeletal muscles. We first generated transgenic mice overexpressing calpain 10 either in pancreatic β cells or in skeletal muscles. We also generated conventional calpain 10 knock-out mice in collaboration with the University of Chicago. While calpain 3 knock-out mice had been generated by another group and were provided for us for phisiological analyses, we could not obtain any significant data that would relate calpain-3 with type 2 diabetes.
On the other hand, higher increase in body weight and insufficiency of early insulin secretion after glucose intake were observed with the transgenic mice of calpain 10 overexpression in pancreatic β cells. We performed real-time PCR using pancreatic islets isolated from these transgenic mice in order to examine the expression level of known MODY genes and diabetes related molecules, resulting in the identification of significant change of Glut2 which is involved in the HNF cascade. We also succeeded in generating calpain 10 knock-out mice and demonstrated that calpain 10 mediated ryanodine-induced apoptosis induced by the fatty acid palmitate and low glucose. Finally we generated transgenic mice overexpressing human calpastatin and found that inhibition of calpain activity in muscle is associated with increases in GLUT4 protein and muscle mass.
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