| Project/Area Number |
14207098
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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 | Showa University |
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Principal Investigator |
KUDO Ichiro Showa University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (30134612)
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| Co-Investigator(Kenkyū-buntansha) |
NAKATANI Yoshihito Showa University, School of Pharmaceutical Sciences, Assistant, 薬学部, 講師 (80266163)
SHIMABARA Satoko Showa University, School of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (60266161)
KUWATA Hiroshi Showa University, School of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (80286864)
村上 誠 昭和大学, 薬学部, 助教授 (60276607)
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| Project Period (FY) |
2002 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥49,920,000 (Direct Cost: ¥38,400,000、Indirect Cost: ¥11,520,000)
Fiscal Year 2005: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2004: ¥14,690,000 (Direct Cost: ¥11,300,000、Indirect Cost: ¥3,390,000)
Fiscal Year 2003: ¥14,690,000 (Direct Cost: ¥11,300,000、Indirect Cost: ¥3,390,000)
Fiscal Year 2002: ¥15,600,000 (Direct Cost: ¥12,000,000、Indirect Cost: ¥3,600,000)
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| Keywords | phospholipase A2 / phospholipid / arachidonate metabolism / knockout mice / transgenic mice / lipoprotein / metabolic syndrome / inflammation / ホスホリパーゼA_2 / トランスジェニックマウス / アラキドン酸 / PGE_2 / 免疫組織化学 / アデノウイルス / リゾホスファチジルコリン / 肺サーファクタント / 癌 / ホスホリパーゼA2 / PGE2 / 肺炎 / リウマチ / 雄性生殖器 / 分泌性PLA2 / 細胞質PLA2 / Ca2+非依存的PLA2 |
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| Research Abstract |
More than 20 phospholipase A_2 (PLA_2) enzymes, which hydrolyze the sn-2 position of glycerophospholipids to liberate fatty acids and lysophospholipids, have been identified in mammals. This study aims to clarify the functions of individual PLA_2 enzymes. In this year, we examined the functions of two secretory PLA_2 (sPLA_2) isozymes in vivo using their transgenic (Tg) and knockout (KO) mice.
On the basis of our recent finding that group X sPLA_2 (sPLA_2-X) is located in peripheral neuronal fibers, we herein looked for some neuronal phenotypes in sPLA_2-X KO mice. We found that the pain nociception induced by intraperitoneal administration of acetic acid was significantly reduced in sPLA_2-X KO mice as compared with that in replicate wild-type (WT) mice. Conversely, enhanced pain response was observed in sPLA_2-X Tg mice relative to that in WT mice. Immunohistochemistry revealed that the immunoreactive sPLA_2-X staining was found in the sciatic nerve fibers as well as in dorsal root ga
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nglions adjacent to the spinal cord. We therefore speculate that the neuron-associated sPLA_2-X may play a regulatory role in the neuronal transmission through as yet unknown mechanisms.
We found that group III sPLA_2 (sPLA_2-III) Tg mice displayed altered plasma lipoprotein composition manifested by decreased HDL and increased modified LDL levels, an event that is generally believed to be linked to atherosclerosis. The view that sPLA_2-III might be involved in the process of atherosclerosis was further supported by immunohistochemical observation that sPLA_2-III immunoreactivity was found in the atherosclerotic lesions in humans as well as those in apoE-deficicent mice. Moreover, sPLA_2-III Tg mice fed with high-fat diet exhibited obesity relative to replicate WT mice. In addition to these metabolic syndrome-like phenotypes, passive cutaneous anaphylactic reaction was elevated in sPLA_2-III Tg mice relative to replicate WT mice, and splenomegaly and dermatitis occurred spontaneously and progressively in aged sPLA_2-III Tg mice, suggesting unexplored actions of sPLA_2-III on the immune system. Finally, we have succeeded in generating sPLA_2-III-deficient mice, which will unveil the physiological relevance of the aforementioned pathogenic aspects observed in sPLA_2-III Tg mice. Less
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