Studies on molecular mechanisms of polyglutamine diseases and its treatment with molecular
| Project/Area Number |
17590903
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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 |
Neurology
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
HATAYAMA Takumi Kyoto Pharmaceutical University, Department of Biochemistry, Professor, 薬学部, 教授 (10094484)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAGISHI Nobuyuki Kyoto Pharmaceutical University, Department of Biochemistry, Lecturer, 薬学部, 講師 (60298685)
SAITO Youhei Kyoto Pharmaceutical University, Department of Biochemistry, Research associate, 薬学部, 助手 (90411032)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Polygultamine disease / Molecular chaperone / Apoptosis / Hsp105 / Hsp-inducing drug / 脳神経疾患 / 熱ショックタンパク質 / Hsp誘導剤 |
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| Research Abstract |
(1)Heat shock proteins (Hsp) are involved in the pathophysiology of several diseases such as cancer, diabetes and neurodegenerative disorders, the small molecules that influence the level of Hsp are expected to be useful for the treatment of various diseases. We have shown that sodium salicylate (SA) activates the heat shock promoter and induces the expression of Hsp. In this study, we examined the functional groups of SA necessary for the induction of Hsp, and revealed that the phenylic hydroxyl group but not carboxyl group of SA seemed to be necessary for the induction of heat shock response. Among these compounds, salicylalcohol that strongly induced the expression of Hsp70 suppressed the protein aggregation and apoptosis caused by an expanded polyglutamine tract in a cellular model of polyglutamine disease. Therefore, some derivatives of SA may be used for the protection of cells against deleterious stressors and neurodegenerative diseases.
(2)Hsp 105 is a molecular chaperone which is highly conserved in organisms from yeast to human and is expressed in various tissues of mammals, but especially at high levels in brain. We have shown that over-expression of Hsp105 suppresses apoptosis caused by an expansion of polyglutamine and expression of Hsp 105 in brain may provide an effective therapeutic means for CAG repeat diseases. In this study, we examined the inhibition mechanisms of apoptosis caused by an expansion of polyglutamine by Hsp 105 and revealed that Hsp 105 inhibited the apoptosis by suppressing the nuclear aggregation of the protein and the nuclear localization of Hsp 105 was necessary for the inhibition of apoptosis. These findings may aid in the development of novel effective drug for the treatment of polyglutamine diseases.
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Report
(3 results)
Research Products
(16 results)
