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Treatment of Ischemic InjuryProf. Yoshikazu Higami
Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences |
"A novel chemotherapeutic strategy of Parp1 inhibitor for ischemic injury." |
Parp1 is a major enzyme catalyzing poly(ADP-ribosyl)ation. It cleaves NAD+ to generate ADP and ADP-ribose which is then added to acceptor proteins through a process of ADP-ribosylation. Over-activation of Parp1 decreases cellular NAD+ and ATP levels, resulting in necrotic cell death caused by breakdown of energy metabolism. Parp1 is also involved in inflammatory responses via NF-kB transactivation. Ischemia/reperfusion- induced Parp1 over-activation is mediated by production of ROS and is involved in NF-kB transactivation. Therefore, Parp1 is an attractive target of protection from ischemia/reperfusion injury. Recently, several Parp inhibitors are being evaluated in clinical trials. However, the existent PARP inhibitors resemble the NAD+ moiety and are designed to competitively block the catalytic domain of the PARP enzyme.
Compound A is an Mdm2 inhibitor and is potent to stabilize tumor suppressor p53. We found that Compound A decreased the Parp1 protein levels. This decrease was not associated with cell death and not observed in p53 deficient cells. Moreover, Compound A -induced reduction of Parp1 protein was mediated with ubiquitin-associated proteasomal degradation probably via MDM2.
The present invention regarding to Compound A -associated Parp1 degradation is to provide a novel chemotherapeutic strategy of Parp1 spedific inhibitor.
1. Development of novel Parp1 inhibitor
2. Screening system of compounds which induce degradation of Parp1
Advantages
1. higher p53 dependency
2. higher Parp1 specificity
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1990-1992: Visiting instructor, Department of Physiology, The University of Texas, Health Science Center at San Antonio, Tx
1992-1993: Instructor, Department of Pathology, Nagasaki University School of Medicine, Japan
1994-2007: Assistant and Associate professor
2007-present: Professor, Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science
2001-2003: Visiting scientist, Department of Medicine, University of Wisconsin, Madison, WI
inquiry Technology Licensing Organization International Division
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Yasunobu Funakoshi
E-mail: funakoshi_yasunobu@admin.tus.ac.jp