| Project/Area Number |
04454556
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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 |
内分泌・代謝学
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| Research Institution | University of Tokyo |
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Principal Investigator |
KODAMA Tatsuhiko University of Tokyo, M.D.Ph.D., 医学部・(病), 助手 (90170266)
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| Co-Investigator(Kenkyū-buntansha) |
KURIHARA Yukiko University of Tokyo, M.D., 医学部・(病), 医員
KURIHARA Hiroki University of Tokyo, M.D.Ph.D., 医学部・(病), 助手 (20221947)
MATSUHASHI Nobuyuki University of Tokyo, M.D.Ph.D., 医学部・(病), 助手 (10221590)
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| Project Period (FY) |
1992 – 1993
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| Project Status |
Completed (Fiscal Year 1993)
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| Budget Amount *help |
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 1993: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1992: ¥4,900,000 (Direct Cost: ¥4,900,000)
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| Keywords | Macrophage / scavenger receptor / cholesterol / ES cell / recombination / transgenic mouse / LDL / antioxidant / アテローム性動脈硬化 / マウス発生工学 / 相同組換え / ES細胞 / エンドセリン / 遺伝子欠損動物 |
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| Research Abstract |
In order to elucidate the physiological role of macrophage scavenger receptors and to develop the novel method to prevent the atherosclerotic disorders, we have applied the mouse developmental biological techniques to vascular biology research.
1) Application of homologous recombination using ES cells to vascular biology : Macrophage scavenger receptor gene and endothelin 1 gene were disrupted in ES cells using homologous recombination. Endothelin 1 gene disruption was transmitted to germ line cells, and endothelin-1 deficient mice strains were established. Initial experiments using ES cells disrupted macrophage scavenger receptor gene failed to be transmitted to germ cells. In order to overcome this obstacle, we improved following points. At first, the ES cell colonies in which the target genes were disrupted, the karyotype analysis is useful. If more than 50% of cells in the colony indicate 2n=50, these cells indicate higher rate of germ cell transmission. Secondary, adding to the injection into blastocysts, we succeeded in the germ cell transmission using co-culture method.
2) Transgenic model for vascular biology research : In order to establish the mouse model for vascular biology, mouse strains overexpressing CETP and macrophage scavenger receptors were established. Using these strains mouse model of atherosclerosis were studied, and using the genetic background of C57BL6 with or without high cholesterol diet, the process of atherogenesis was studies.
3) Analysis and screening of drugs preventing atherogenesis using mouse genetics. The drug which can prevent the cholesterol accumulation through scavenger pathway were screened using these mouse model. In order to prevent the atherogenesis, LDL antioxidant should satisfy following conditions ; a) The drug should locate within atherogenic lipoproteins, b) In LDL the drug can move to core lipid region, and c) the drug can prevent the biological oxidation including that by lipoxygenase.
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