| Project/Area Number |
15K08947
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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 |
Gastroenterology
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| Research Institution | University of Toyama |
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Principal Investigator |
Sugiyama Toshiro 富山大学, 大学院医学薬学研究部(医学), 特任教授 (00196768)
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| Co-Investigator(Kenkyū-buntansha) |
三原 弘 富山大学, 大学院医学薬学研究部(医学), 助教 (00612623)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 非ステロイド系抗炎症剤 / 小腸潰瘍 / 透過性亢進 / TRPV4 / 非ステロイド系抗炎症薬 / 細胞膜透過性亢進 / TRPV4阻害薬 / NSAIDｓ / 細胞膜透過性 / NSAIDｓ小腸潰瘍 / NSAIDs / 細胞透過性 |
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| Outline of Final Research Achievements |
NSAIDs-induced small intestinal ulcerations are rapidly increasing, however the effective prevention has not been established. As the ulcerations are prevented by the use of broad spectrum antibiotics, the intestinal inflammation by intestinal flora or the metabolites should be attributed. However, the molecular mechanism related to increased permeability of small intestinal epithelial cells by NSAIDs use is not elucidated.
By the permeability experiment with small intestinal epithelial cells, NSAIDs accelerated the permeability via the accumulation of 8, 9 EET, which is the metabolites of membrane arachidonic acids and activated TRPV4. The activated TRPV4 is attributed to the increase of permeability. By this assay system, one candidate drug was selected, which showed the inhibition of TRPV4 activation and inhibited the increased permeability of intestinal epithelial cells induced by NSAIDs. Clinical trials are planning to confirm the preventing effect of the candidate.
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| Academic Significance and Societal Importance of the Research Achievements |
NSAIDｓ小腸潰瘍の効果的な予防法はなく、その形成機序の研究から小歌的な予防法の確立が期待されている。NSAIDｓ小腸潰瘍形成には腸内細菌あるいは腸内細菌関連炎症惹起因子の小腸組織内侵入が重要であり、それに関わる上皮細胞膜透過性亢進の詳細な分子機序の解明が新たな予防戦略の道を切り開く。
本研究から小腸上皮細胞膜透過性亢進にはイオンチャネルであるTRPV4活性化が引き金であり、ある既存薬（米国で発売、他疾患治療に使用されている）がNSAIDｓによるTRPV4活性化、細胞膜透過性亢進を阻害することが明らかとなり、新規のNSAIDｓ起因性小腸潰瘍予防薬として有望であり、臨床試験が計画中である。
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