| Project/Area Number |
18390077
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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 |
General pharmacology
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| Research Institution | Keio University |
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Principal Investigator |
MATSUOKA Masaaki Keio University, School of Medicine, Associate Professor (70222297)
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| Co-Investigator(Kenkyū-buntansha) |
CHIBA Tomohiro KEIO University, School of Medicine, Assistant Professor (60398617)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,720,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥1,920,000)
Fiscal Year 2007: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
Fiscal Year 2006: ¥8,400,000 (Direct Cost: ¥8,400,000)
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| Keywords | Alzheimer's disease / TGFbeta2 / Neuronal cell death / Colivelin / Defense factor / Humanin |
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| Research Abstract |
In our earlier studies, we demonstrated that TGFbeta2 is a putative natural ligand of APP inducing Alzheimer's disease's related neuronal death (TGFbeta2 theory) and Humanin may be a specific endogenous neuroprotective polypeptide inhibiting Alzheimer's disease's relevant neuronal death (defense theory). The first purposes of this project have been to obtain evidence supporting the TGFbeta2 theory of Alzheimer's disease's related neuronal cell death and the defense theory of Alzheimer's disease. The second purpose has been to conduct preclinical research to develop Humanin or a Humanin's derivative Colivelin as neuroprotective drugs to Alzheimer's disease. Using immunohistochemistry and molecular biological techniques, we have first shown that TGFbeta2 expression levels were upregulated in brains of autopsied Alzheimer's disease cases. In addition, we have identified MOCA and POSH as a putative mediators linking PS1 and the TGFbeta2-triggered death signal pathway. These results strongly support our TGFbeta2 theory. Second, we identified a Humanin receptor on the cell membrane and elucidated that in addition to the JAK2/STAT3 pathway, a PI3 kinase pathway was activated by Humanin. Identifing 4k1) and 10kD endogenous Humanin-like peptides, we are also now trying to identify the primary structure of endogenous Humanin-like peptides. Finally, we have succeeded in showing that Colivelin inhibits memory impairment in Alzheimer's disease transgenic mouse models Tg2576 mice aged 15 months. All these results indicated that Humanin or Humanin-like peptides exist as an endogenous defense factor and that neuroprotective therapy with Humanin may be effective against Alzheimer's disease.
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