| Project/Area Number |
16390037
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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 | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
OHTSUKI Sumio Tohoku University, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院薬学研究科, 助教授 (60323036)
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| Co-Investigator(Kenkyū-buntansha) |
TERASAKI Tetsuya Tohoku University, Graduate School of Pharmaceutical Sciences, Professor, 大学院薬学研究科, 教授 (60155463)
KAMIIE Junichi Tohoku University, Graduate School of Pharmaceutical Sciences, Lecturer, 大学院薬学研究科, 助手 (10400269)
淺島 朋子 東北大学, 大学院・薬学研究科, 助手 (00400268)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2006: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2004: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | Blood-Brain Barrier / Blood-Cerebrospinal Fluid Barrier / Neurotoxin / Efflux transport / ABC transporter / Cholesterol / Disease / Regulation / ABCA1 / ABCG2 / 脳脊髄液関門 / キノリン酸 / 脳内局在 |
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| Research Abstract |
Transport system at the blood-brain barrier plays important role in drug distribution into the brain. The purpose of this project was to clarify the new transport system at the blood-brain barrier as CNS elimination system for neurotoxins.
24(S)-hydroxycholesterol is a major metabolite of CNS cholesterol and its accumulation induces the neurotoxic effect. We have clarified that 24(S)-hydroxycholesterol was eliminated from the brain across the blood-brain barrier by carrier-mediated transport system, and oatp was likely to be involved in this efflux transport system. This result exploded the established hypothesis that 24(S)-hydroxycholesterol traverses the blood-brain barrier by simple diffusion.
We also clarified that 24(S)-hydroxycholesterol induced the expression and function of cholesterol transporters, ABCA1 and ABCG1, at the blood-cerebrospinal fluid barrier. The cholesterol release from choroid plexus epithelial cells by these transporters was affected by the subtype of apolipoprotein E (ApoE). Subtype of ApoE was reported as a risk factor of Alzheimer's diseases. Therefore, this regulation system is likely to has a relation to progression of Alzheimer's diseases.
We analyzed the regulation mechanism of transporters at the blood-brain barrier, and clarified that OAT3 expression at the blood-brain barrier was regulated by androgen receptors. Furthermore, hyperammonia, which is often observed in acute liver failure, affected the expression and function of creatine transport and taurine transport at the blood-brain barrier.
This result indicates the physiological role of the blood-brain barrier transport system for supporting brain function. This evidence provides important information to understand the blood-brain barrier transport system not only as drug delivery pathway but also as target for drugs.
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