| Project/Area Number |
17590045
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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 |
Physical pharmacy
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| Research Institution | Osaka University of Pharmaceutical Sciences |
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Principal Investigator |
ISHIDA Toshimasa Osaka University of Pharmaceutical Sciences, Pharmacy, Professor (00111021)
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| Co-Investigator(Kenkyū-buntansha) |
TOMOO Koji Osaka University of Pharmaceutical Sciences, Pharmacy, Associate Professor (70257898)
IN Yasuko Osaka University of Pharmaceutical Sciences, Pharmacy, Research Assistant (50257896)
MINOURA Katsuhiko Osaka University of Pharmaceutical Sciences, Pharmacy, Research Assistant (10278591)
TANIGUCHI Taizo Kobe University, Bio-signal Research Center, Lecturer (70346253)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,710,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | tau protein / microtubule-bindine domain / filament formation / self-aggregation / Alzheimer' disease inhibiting drug / 微小管結合ドメイン / マイクロチュブル結合ドメイン / 自己重合 |
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| Research Abstract |
1) Identification of repeat region and amino acids responsible for self-association of tau microtubule-binding domain
Among the four repeated structures of tau microtubule-binding domain (MBD), it was elucidated that the second and third repeats, especially the linkage of the second and third repeats, are most responsible for the self-aggregation of MBD, and N-terminal Lys of the second repeat and the Tyr and Pro residues of the third repeat are essential for the aggregation. Concerning the function of the first and fourth repeats, it was clarified that the fourth repeat exerts potent aggregation ability in an acidic solution, but not in a neutral solution, whereas the first repeat acts as repressor in both of neutral and acidic solutions.
2) Development of compounds inhibiting self-aggregation of tau MBD
On the basis of insights of 1), various compounds that inhibit self-aggregation of tau MBD were investigated, and consequently, some single DNA molecules, methylene blue and cyanidin were shown to exhibit potent inhibiting ability for the MBD aggregation. The detailed analysis on the inhibition mechanism of these compounds is now in progress.
3) Preparation of antigens that recognize repeated structures of MBD and the evaluation of their inhibition for MBD self-aggregation
Monoclonal antibodies against the 1st or 2nd repeat of the microtubule binding domain, but not the C-terminal 16 residues, completely inhibited tau aggregation into PHF. Furthermore, they did not inhibit tau-induced tubulin assembly. Thus, they are useful to investigate tau protein conversion and will be useful therapeutic lead materials.
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