| Project/Area Number |
60480142
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Medical College of Oita |
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Principal Investigator |
KUWANO Michihiko Medical College of Oita, Professor, 医学部, 教授 (80037431)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAKI Ryosaburo Medical College of Oita, Professor, 医学部, 教授 (90038620)
ONO Mayumi Medical College of Oita, Research Associa, 医学部, 助手 (80128347)
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| Project Period (FY) |
1985 – 1986
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| Project Status |
Completed (Fiscal Year 1986)
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| Budget Amount *help |
¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 1986: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1985: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | Low Density Lipoprotein / Low Density Lipoprotein Receptor / Receptor Disease / Abnormal Cholesterol Metabolism / Somatic Cell Genetic Mutants / Hypercholesterolemia / Endocytosis / 高脂血症 |
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| Research Abstract |
* Cellular uptake of low density lipoprotein (LDL) is mediated through receptor mediated endocytosis. Familiar hypercholesterolemia is closely linked to a number of mutations which distort the transport and processing of LDL receptors. To understand pathological changes in sterol metabolism in relation to receptor-mediated endocytosis of LDL, somatic cell mutants with altered sterol metabolism could be valuable. In particular, we try to propose such somatic cell mutants as model cell for abnormal sterol metabolic diseases. In this study we have studied three different mutants with altered receptor-mediated pathway of LDL.
1. Monensin-resistant mutant of Chinese hamster overy (CHO) cells was defective in LDL binding to the cell surface receptor. This mutant showed higher sterol synthesis in the presence of LDL than CHO cells, and defective down-regulation of LDL receptors was observed in the mutant. N-linked glycosylation appeared to be altered among N- and O- linked oligosaccharides associated with LDL receptors in the mutant, suggesting altered function of Golgi apparatus.
2. Monensin-resistant mutant of mouse Balb/3T3 cells was defective in endocytosis of LDL. This mutant also showed poor down-regulation of function of Golgi function appears to cause change(s) of membranous component, which may affect the endocytosis of LDL.
3. Compactin-resistant mutant of Chinese hamster V79 cells was defective in LDL-receptor as well as endocytosis of LDL. LDL receptor synthesized in the mutant showed truncated molecules with aberrant O-linked sugar glycosylation.
The turnover of mutant LDL receptors was much faster than that of wild ones, suggesting that the receptor molecules lacking O-linked sugars is sensitive to protease action.
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