| Project/Area Number |
16K10001
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
Ishigaki Keiko 東京女子医科大学, 医学部, 准教授 (10366304)
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| Co-Investigator(Kenkyū-buntansha) |
池田 真理子 (谷口) 藤田医科大学, 大学病院, 准教授 (00410738)
竹内 敦子 神戸薬科大学, 薬学部, 准教授 (80154970)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | 福山型先天性筋ジストロフィー / プロスタノイド / ドラッグリポジショニング / アスピリン / H-PGDS阻害薬 / ステロイド / アラキドン酸カスケード / 尿中プロスタグランジン代謝産物 / シクロオキシゲナーゼ阻害薬 / フクチンマウス |
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| Outline of Final Research Achievements |
Fukuyama congenital muscular dystrophy (FCMD) patients show significantly elevated prostaglandin (PG) D2 and E2 metabolites in urine samples as compared with normal controls. These PGD2 and PGE2 metabolites were increased in patients with typical and severe phenotypes, suggesting clear correlations with phenotype. Scattered expressions of hematopoietic PGD synthase and microsomal PGE synthase-1 were detected in some necrotic fibers from patients with FCMD. These observations suggested that prostanoid may have an important role in the pathogenesis of FCMD, as it does in Duchenne muscular dystrophy. FCMD model mice also had significantly elevated PGD2 metabolites. We gave FCMD model mice low and high doses of aspirin as a potential therapy. The urinary PGD2 and E2 metabolite levels tended to decrease but, even in the high-dose group, the differences did not reach statistical significance, and aspirin administration did not produce clear pathological changes in muscles.
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| Academic Significance and Societal Importance of the Research Achievements |
FCMDは，脳奇形合併を特徴とする重度の筋ジストロフィーであるが，治療法はまだない．DMDでは筋壊死にPGD2の関与が示唆され，治療薬として造血器型PGD合成酵素阻害薬が治験実施中であるが，FCMDではPGDの関与が低く対象外とされてきた．本研究では，FCMD患者において，臨床病型の重症度と一致して，PG尿中代謝物が有意に増加しており，かつ筋壊死線維にPG合成酵素の発現がみられたことから，FCMDの候補治療薬として，PGD合成酵素阻害薬などアラキドン酸カスケードを阻害する薬剤が候補となりうることが示された．疾患モデルマウスへのアスピリン投与を試みたが，今回は有効性の証明には至らなかった．
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