Control of the drug efflux transport from the brain utilizing the transport function for the large molecules〜
| Project/Area Number |
11672270
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Hokkaido College of Pharmacy (2000)
University of Shizuoka (1999) |
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Principal Investigator |
DEGUCHI Yoshiharu Hokkaido College of Pharmacy, Department of Biopharmaceutics, Assistant Professor, 薬学部, 講師 (40254255)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1999: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Keywords | Blood-Brain Barrier / Drug Efflux Transport / Basic Fibroblast Growth Factor / Endocytosis / Immortalized Culture Cells / Heparan Sulfate Proteoglycan / FGF Receptor / Transport for Large Molecule / 血管脳関門 / 血管脳関門排出輸送 / ヘパリン / トランスサイトーシス / 脳灌流法 |
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| Research Abstract |
The final goal of this study is to control the expression of drug efflux transporter in the blood-brain barrier (BBB) and to improve the brain transferability of the drug. There is the possibility of suppressing the efflux transporter by introducing the antibody and/or antisense gene in the brain capillary endothelial cell. However, these giant molecule does not BBB easily. Some bioactive peptides and proteins are exceptionally taken up by the brain through the specialized transportation system of the BBB.If such transport system is utilized, antisense gene may be delivered into the brain capillary endothelial cells. However, information on the peptide/or protein transport system in the BBB is limited, In this study, the researcher clarified for the first time that heparan sulfate proteoglycan (HSPG) of the BBB functions transport system of large molecules including bioactive peptides and proteins.
Using conditionally immortalized mouse brain capillary endothelial cell lines (TM-EBB), i
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t was confirmed that the gene expression of mouse perlecan which is the core protein of HSPG is expressed at TM-BBB.Next, the transport function of HSPG is examined using ^<125>l-bFGF as a ligand to HSPG.^<125>l-bFGF avidly bound to the brain capillary isolated from the bovine brain. Internalization of ^<125>l-bFGF into TM-BBB showed concentration-dependence, temperature and osmolarity dependence. In addition, the internalization was significantly inhibited in heparin, chondroitin sulfate B, and it was also inhibited in cells treated with heparinase and sodium chlorate, and antibody to mouse perlecan. In situ brain perfusion of ^<125>l-bFGF revealed the uptake into the brain parenchyma of unchanged ^<125>l-bFGF.This brain uptake of ^<125>l-bFGF was significantly inhibited by the heparin co-perfusion. From these results, it became clear that HSPG is expressed in the BBB and that it functions as the transport system of large molecule to the brain. By utilizing this transport system in future, antibody and/or antisense gene, which controls the function of the efflux transporter in the BBB, may be efficiently delivered into the brain endothelial cells. Less
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Report
(3 results)
Research Products
(9 results)
