| Project/Area Number |
23790201
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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 | Tokyo University of Science |
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Principal Investigator |
OKITA Naoyuki 東京理科大学, 薬学部, 助教 (60453841)
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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 |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2011: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
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| Keywords | PARP1 / Nutlin3a / Caylin2 / 虚血再灌流障害 / p53 / プロテアソーム / Parp1 / Nutlin-3a |
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| Research Abstract |
PARP1 is an important enzyme involved in various patho-physiological phenomena such as ischemia/reperfusion (I/R) injury, which occurs when blood flow is restored after cerebral infarction, myocardial infarction and transplantation of various organs. I/R-induced PARP1 over-activation is mediated by production of reactive oxygen species and is involved in NF-κB transactivation. For these reasons, PARP1 is an attractive target for strategies to protect against I/R injury. Because we found that Nutlin-3a, an MDM2 inhibitor, treatment reduces the protein levels of PARP1 in culture cells, we investigated the novel regulatorymechanism of PARP1 for development of therapeutic agents for ischemia/reperfusion injury. Consequently we obtained the results that Nutlin-3a and its analogue Caylin-2 treatment induce proteasomal degradation of PARP1 in a p53-dependent manner, and the down-regulation of PARP1 is reversible and accompanied with an inflammatory response. For protection against I/R injury, our results support the usability of the p53 inducible cis-imidazoline compounds, Nutlin-3a and its analogs, as PARP1 inhibitors.
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