| Project/Area Number |
19790347
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Virology
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| Research Institution | National Institute of Infectious Diseases |
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Principal Investigator |
ARITA Minetaro National Institute of Infectious Diseases, ウイルス第二部第二室, 主任研究官 (70356244)
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| Project Period (FY) |
2007 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥3,720,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥720,000)
Fiscal Year 2010: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2009: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2008: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2007: ¥600,000 (Direct Cost: ¥600,000)
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| Keywords | 病原性 / ポリオウイルス / ポリオ後症候群 / 残存性麻痺 / 複製 / 阻害剤 / スクリーニング / 擬似ウイルス / マウスモデル |
|---|
| Research Abstract |
We established a mouse model that shows residual poliomyelitis-like paralysis by using poliovirus (PV) pseudovirus infection in PV receptor-expressing mouse (TgPVR21), and analyzed a long-term effect of paralysis in the mice. To identify\y possible host factor required for post-polio syndrome, we searched for ant-PV compounds that inhibit replication process of PV. TgPVR21 mice showed severe residual poliomyelitis-like paralysis after inoculation with PV pseudovirus of more than 4.1×10^6 infectious units. After 6 months with/without exercise stress, we could not identify post-polio like symptom that could be attributable to the paralysis and exercise stress. We identified GW5074 (Raf-1 inhibitor) as PV replication inhibitor, and several kinase inhibitors, including MEK1/2 inhibitors, EGFR inhibitor, PI3K inhibitor, that could cooperatively act with GW5074 to inhibit PV replication. We found that the viral resistance determinant to GW5074 was a similar mutation to an anti-picornavirus compound enviroxime with unknown inhibitory mechanism. Moreover, we identified phosphatidylinositol 4-kinase III beta (PI4KB) as the target of GW5074 for its anti-PV activity, and indicated that PI4KB is a target of enviroxime-like compounds for its anti-PV activity.
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