1991 Fiscal Year Final Research Report Summary
Establishment of CTX Model Animal and Survey of its Pathogenesis.
| Project/Area Number |
02454154
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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 | University of Tokyo |
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Principal Investigator |
SEYAMA Yousuke University of Tokyo, Department of Physiological Chemistry and Nutrition, Professor, 医学部(医), 教授 (90010082)
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| Co-Investigator(Kenkyū-buntansha) |
KASAMA Takeshi Tokyo Medical and Dental University, Laboratory for Biochemical Analysis, Associ, 医学部, 助手 (80124668)
SHIMIZU Takao University of Tokyo, Department of Biochemistry, Professor, 医学部, 教授 (80127092)
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| Project Period (FY) |
1990 – 1991
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| Keywords | Cerebrotendinous Xanthomatosis / Model Animal / Cholestanol / Gallstone / Band Keratopathy |
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| Research Abstract |
Cerebrotendinous xanthomatosis (CTX) is a hereditary sterol storage disease which is characterized by the increase in the cholestanol content in the serum and various organs. In order to elucidate the pathogenesis of CTX, mice were fed with a diet rich in cholestanol. The concentrations of sterol in the serum, liver, and cerebellum were determined using HPLC. (1) In the cholestanol-fed mice, the cholestanol concentrations in the serum and liver reached maxima in the first 2 to 4 weeks. Cholestanol concentration declined thereafter, finally to 50-60 % of the maxima. On the other hand, the levels of cholestanol in the cerebellum increased almost linearly in parallel to the feeding time, and no decline was observed. These results suggest that the capacity of the liver to remove or degrade cholestanol was increased by long-term intake of this compound, whereas the cerebellum had no such feed-back regulation. Histological examinations using an electron microscops revealed the enlargement of
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lysosomal granules in the liver of the cholestanol-fed mice. (2) Two kinds of corneal opacities resembling calcific band keratopathy in human were also found in 20 % of these cholestanolfed mice. The crystal particles were observed between epithelial basement membrane and superficial stroma by the electron microscopy. Energy dispersive analysis of the materials, which was presumed to be cholestanol. These results suggest that the cholestanol may deposit in the cornea from elevated serum levels. Deposition of cholestanol in cornea and related area may be a cause of corneal dystrophy in CTX. (3) After feeding cholestanol diet for 14 months, gallstones composed of 55 % cholesterol and 45 % cholestanol developed in 20 % of the mice and were associated with gallbladder mucosal inflammation and serosal vessel thickening. Experimental data demonstrate that cholestanol replaces cholesterol in serum and liver, causes increased cholestanol biosynthesis, but inhibits bile acid synthesis. The combination of these phenomena promotes gallstone formation in cholestanol-fed mice. These three findings proof the usefulness of this model animal in the investigation of CTX pathogenesis. Less
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