| Budget Amount *help |
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2005: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2004: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2003: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Research Abstract |
It is widely accepted that effects of nonsteroidal anti-inflammatory drugs (NSAIDs) result from inhibition of cyclooxygenase (COX) activities. COX has two isoforms, constitutive enzyme COX-1 and inducible enzyme COX-2. COX-2 selective inhibitors are considered as promised NSAIDs with low side effects derived from inhibition of COX-1 activity. However, recent reports show COX-2 selective inhibitors have also side effects such as increase risk of serious coronary heart disease, indicating a growing need for searching other drug targets. As one of the novel targets, microsomal prostaglandin E synthase (mPGES) is noteworthy because it is more selectively induced than COX-2 in inflammatory sites. On the other hand, 5-lipoxygenase activating protein (FRAP), a member of the same family of mPGES, and peroxisome proliferator-activated receptor (PPAR), a member of nuclear receptor superfamily, are recognized as drug targets against lifestyle-related diseases. We found that resveratrol, a polyphenol contained in red wines, is a dual agonist for PPARα and γ, and that resveratrol protects the brain against ischemia by activation of PPARα. Remarkably, MK-886, a dual inhibitor for mPGES and FLAP is reported to be a PPARα antagonist, indicating the possibility of the side effect of mPGES inhibitor by its antagonistic activity for PPAR. The aim of this study is to determine the three-dimensional structures of mPGES, FLAP and PPARα for development of novel drugs based on their structures. We successfully expressed and purified these recombinant proteins, and are still investigating the conditions for their good crystallization. We obtained a protein crystal for FLAP by the lipidic cubic phase method, which is a newly developed.
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