| Project/Area Number |
24591016
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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 | Kumamoto University |
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Principal Investigator |
OHMURAYA Masaki 熊本大学, 生命資源研究・支援センター, 准教授 (60398229)
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| Co-Investigator(Renkei-kenkyūsha) |
ARAKI Kimi 熊本大学, 生命資源研究・支援センター, 教授 (90211705)
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| Project Period (FY) |
2012-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 慢性膵炎 / 膵星細胞 / SPINK1/Spink3 / オートファジー / ネクロプトーシス / リポソーム / クロドロネート / Pancreatic stellate cell / Liposome / Chronic pancreatitis |
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| Outline of Final Research Achievements |
Mutations in SPINK1 are associated with chronic pancreatitis (CP). Genetic deletion of Spink3, mouse homolog of SPINK1, causes postnatal lethality precluding mechanistic investigations into the effects of SPINK deficiency. Here we have developed SPINK1 knockin in mice by cre-loxP technology (termed “SPINK1-X-in” and “SPINK1- in”). This partial restoration of SPINK function rescues mice from lethality, but, in contrast to control mice, SPINK1-X-in and SPINK1- in mice within 4 weeks developed pancreas damage the earliest manifestations of which were impaired autophagy and increased trypsin activity, and these mice progressively develop spontaneous chronic pancreatitis. SPINK1-in mice represent a novel, clinically relevant, genetic model of human CP, revealing the mechanisms whereby SPINK insufficiency causes CP. The results identify new targets of SPINK regulating autophagic and lysosomal pathways in pancreas.
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