| Project/Area Number |
09307052
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 | KYOTO UNIVERSITY |
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Principal Investigator |
ICHIKAWA Atsushi Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Professor, 薬学研究科, 教授 (10025695)
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| Co-Investigator(Kenkyū-buntansha) |
SUGIMOTO Yukihiko Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Associate Professor, 薬学研究科, 助教授 (80243038)
NEGISHI Manabu Kyoto Univ., Grad. Sch. of Biostudies, Professor, 生命科学研究科, 教授 (60201696)
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| Project Period (FY) |
1997 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥34,700,000 (Direct Cost: ¥34,700,000)
Fiscal Year 1999: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 1998: ¥9,900,000 (Direct Cost: ¥9,900,000)
Fiscal Year 1997: ¥18,100,000 (Direct Cost: ¥18,100,000)
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| Keywords | mast cell / differentiation / histamine / prostaglandins / histidine decarboxylase / prostanoid receptors / knockout mouse / allergic inflammation / EP4受容体 / EP2受容体 / EP2受容体欠損マウス / ヒスチジン脱炭酸酵素欠損マウス / ヒスチジンデカルポキシラーゼ / ヒスチジンデカルボキシラーゼ |
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| Research Abstract |
We established primary culture system of bone marrow-derived mast cells, and examined function of histamine and PGs by monitoring expression of histidine decarboxylase(HDC), PG synthetases, and PG receptors. We found that stimulation of antigen-lgE complexes increase expression of COX-2, EP receptors, IP and DP receptors. In addition, we clarified relationship between intracellular localization of HDC and post-transnational modification; this enzyme is highly-regulated by the proteasome degradation system. From these studies, we found that production of histamine and PGs, and induction of PG receptors are highly-regulated dependent on differentiation of mast cells. These results also suggested that histamine and PGs may take part in differentiation-specific processes of mast cells.
Based on findings described above, we examined physiological roles of PGs and histamine in various systems including mast cell function by using PG receptor-deficient mice and HDC-deficient mice. We establish
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ed mice deficient in each type of prostanoid receptors, and clarified physiological roles of prostanoids by examining phenotypes in each knockout mice : FP-deficient mice fail to deliver their pups due to persistent production of progesterone in ovaries, indicating that PGF2α plays a role in luteolysis required for normal parturition. IP-deficient mice showed increased tendency of thrombosis, reduced responses of inflammation, and did not show acetic acid-induced writhing responses, indicating that PGI2 participates in promotion of inflammation and pain sensation. EP3-deficent mice did not show febrile responses to both endogenous and exogenous pyrogen; PGE2 mediates pyrogen-induced fever generation via EP3. EP4-deficient mice died within three days after birth due to patency of ductus arteriosus. PGE2 plays an essential role in neonatal closure of ductus arteriosus via EP4. EP2-deficent female mice showed reduced fertility due to impaired ovulation and fertilization; PGE2 contributes to ovulation and fertilization through stimulation of cumulus expansion via EP2 and the resultant increase in cAMP level. Through these studies, we demonstrated importance of receptor subtype-specific activities. HDC-deficient mice showed reduced responses in lgE-dependent type l allergy, indicating that histamine is essential in this disease. Less
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