Elucidation of disease-related changes of drug brain distributions based on intrinsic efflux activity and absolute expression level of P-glycoprotein at the brain barrier
| Project/Area Number |
23790170
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Medical pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
UCHIDA YASUO 東北大学, 薬学研究科(研究院), 助教 (70583590)
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| Project Period (FY) |
2011 – 2013
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| Project Status |
Completed (Fiscal Year 2013)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | 血液脳関門 / 病態 / P糖タンパク / 絶対発現量 / 単分子輸送活性 / In vivo機能の再構築 / Caveolin1 / Pharmacoproteomics / 病態血液脳関門 / 炎症 / 定量プロテオミクス |
|---|
| Research Abstract |
This study aimed to establish a methodology to clarify drug efflux function of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in disease conditions. We experimentally demonstrated that, in the disease which the absolute protein expression level of P-gp changes (epilepsy), the in vivo function of P-gp at the BBB can be reconstructed from in vitro by integrating the efflux activity per one P-gp molecule measured in its overexpressing cell lines and the absolute expression level in isolated brain capillaries. We found that, in the disease condition which the efflux activity per one P-gp molecule changes (inflammatory oxidative stress), the phosphorylation level of caveolin1 Tyr14 is one of the biomarkers to estimate the change of the activity. We also demonstrated the reconstruction of P-gp function in monkeys as well as rodents, and opened the new way to clarify the efflux function of P-gp at the human BBB in diseases from in vitro system.
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Report
(4 results)
Research Products
(113 results)
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[Journal Article] Validation of uPA/SCID mouse with humanized liver as a human liver model: protein quantification of transporters, cytochromes P450, and UDP-glucuronosyltransferases by LC-MS/MS2014
Author(s)
Ohtsuki S, Kawakami H, Inoue T, Nakamura K, Tateno C, Katsukura Y, Obuchi W, Uchida Y, Kamiie J, Horie T, Terasaki T
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Journal Title
Drug Metab Dispos
Volume: in press
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Peer Reviewed
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[Journal Article] A Study Protocol for Quantitative Targeted Absolute Proteomics (QTAP) by LC-MS/MS: Application for Inter-Strain Differences in Protein Expression Levels of Transporters, Receptors, Claudin-5, and Marker Proteins at the Blood-Brain Barrier in ddY, FVB, and C57BL/6J mice.2013
Author(s)
Y Uchida, M Tachikawa, W Obuchi, Y Hoshi, Y Tomioka, S Ohtsuki, T Terasaki
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Journal Title
Fluids Barriers CNS
Volume: 10
Issue: 1
Pages: 21-21
DOI
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Peer Reviewed
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[Journal Article] Transcriptomic and quantitative proteomic analysis of transporters and drug metabolizing enzymes in freshly isolated human brain microvessels2011
Author(s)
Shawahna R, Uchida Y, Declèves X, Ohtsuki S, Yousif S, Dauchy S, Jacob A, Chassoux F, Daumas-Duport C, Couraud PO, Terasaki T, Scherrmann JM
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Journal Title
Mol Pharm
Volume: 8(4)
Issue: 4
Pages: 1332-1341
DOI
Related Report
Peer Reviewed
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[Journal Article] Amyloid-βpeptide(1-40) elimination from cerebrospinal fluid involves low-density lipoprotein receptor-related protein 1 at the blood-cerebrospinal fluid barrier2011
Author(s)
Fujiyoshi M., Tachikawa M., Ohtsuki S., Ito S., Uchida Y., Akanuma S., Kamiie J., Hashimoto T., Hosoya K., Iwatsubo T., Terasaki T.
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Journal Title
J. Neurochem.
Volume: 118
Issue: 3
Pages: 407-15
DOI
Related Report
Peer Reviewed
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[Presentation] Targeted Proteomic Absolute Quantification on Transporters of Human Pancreatic Cancer Cells with Gemcitabine-resistance.2013
Author(s)
Y Ueno, S Hoshino, N Tsuchida, S Nakata, Y Uchida, K Sekine, YW Zheng, M Kurata, S Morinaga, Y Miyagi, T Yokose, I Endo, T Terasaki, H Hirano, H Taniguchi
Organizer
Human Proteome Organization (HUPO) 12th Annual World Congress
Place of Presentation
パシフィコ横浜（横浜）
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