2007 Fiscal Year Final Research Report Summary
Analyses of pathophysiological functions of prostaglandin E synthases as a potential target for novel anti-inflammatory drugs
| Project/Area Number |
18390033
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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 |
Biological pharmacy
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| Research Institution | Tokyo Metropolitan Organization for Medical Research |
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Principal Investigator |
MURAKAMI Makoto Tokyo Metropolitan Organization for Medical Research, The Tokyo Metropolitan Institute of Medical Science, Biomembrance Signaling Project, Project Leader (60276607)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMOTO Kei The Tokyo Metropolitan Institute of Medical Science, Biomembrance Signaling Project, Researcher (30304504)
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| Project Period (FY) |
2006 – 2007
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| Keywords | PGE_2 / PGE_2 synthase / knockout mouse / cancer / inflammation / arachidonic acid metabolism / cyclooxygenase / phospholipase A_2 |
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| Research Abstract |
In this study, we examined the pathophysiological roles of PGE_2 synthase (mPGES-1), a terminal PGE_2-biosynthetic enzyme in the arachidonic acid metabolism, using mPGES-1 knockout mice.
1. mPGES-1 and cancer : Luwis lung carcinoma (LLC) cells stably overexpressing mPGES-1 proliferated more rapidly in vitro and, when implanted into C57BL/6 mice, formed larger and more subcutaneous tumors and lung metastatic foci than did parental cells. Conversely, mPGES-knockdown LLC cells produced smaller and fewer tumors in implanted mice mPGES-1-null mice implanted with LLC cells showed resistance to tumor growth and metastasis associated with reduced angiogenesis compared with replicate wild-type mice Moreover, azoxymethanie-induced colon carcinogenesis was markedly reduced in mPGES-1-null mice relative to that in wild-type mice These results indicate that mPGES-1 expressed in tumor cells as well as in host tissues participates in tumorigenesis.
2. mPGES-1 and inflammation : In carageenan- and thioglycolate-induced peritonitis models, leukocyte infiltration was markedly mitigated in mPGES-1-deficient mice as compared with that m control mice.
3. mPGES-1 and bone : mPGES-1 deficiency was associated with impaired fracture healing, but not with bone loss or osteoarthritis, in mouse models of skeletal disorders.
4. mPGES-1 and colitis : Dextran sulfate-induced colitis (a model of inflammatory bowel disease), as evaluated by intestinal histology, bleeding and cytokine expression, was significantly exacerbated in mPGES-1 knockout mice compared with control mice.
Thus, novel drugs that could inhibit mPGES-1 would be useful for treatments of cancer and inflammation, yet they might have some adverse effects on bone and gastrointestinal tract.
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