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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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,520,000 (Direct Cost: ¥15,300,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2007: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2006: ¥7,900,000 (Direct Cost: ¥7,900,000)
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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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Report
(3 results)
Research Products
(95 results)
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[Journal Article] Transgenic expression of group V, but not group X, secreted phospholipase A_2 in mice leads to neonatal lethality because of lung dysfunction.2006
Author(s)
Otsuki, M., Taketomi, Y., Arata, S., Masuda, S., Ishikawa, Y., Ishii, T., Takanezawa, Y., Aoki, J., Arai, H., Yamamoto, K., Kudo, I., Murakami,M.
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Journal Title
J.Biol.Chem. 281
Pages: 36420-36433
Related Report
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[Journal Article] Critical role of PICT-1, a tumor suppressor candidate, in phospatidylinositol 3,4,5-trisphosphate signals and tumorigenic transformation.2006
Author(s)
Okahara, F., Itoh, K., Nakagawara, A., Murakami, M., Kanaho, K., Maehama,T.
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Journal Title
Mol.Biol.Cell. 17
Pages: 4888-4895
Related Report
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[Journal Article] Unique membrane interaction mode of group IIF phospholipase A_2.2006
Author(s)
Wijewickrama, G.T., Albanese, A., Kim.Y.J., Oh, Y.S., Murray, P.S., Takayanagi, R., Tobe, T., Masuda, S., Murakami, M., Kudo, I., Ucker, D.S., Murray, D., Cho,W.
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Journal Title
J.Biol.Chem. 281
Pages: 32741-32754
Related Report
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