Project/Area Number |
18K14583
|
Research Category |
Grant-in-Aid for Early-Career Scientists
|
Allocation Type | Multi-year Fund |
Review Section |
Basic Section 42020:Veterinary medical science-related
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Research Institution | Tokyo Medical and Dental University |
Principal Investigator |
Mami UEMURA 東京医科歯科大学, 統合研究機構, 非常勤講師 (20596001)
|
Project Period (FY) |
2018-04-01 – 2022-03-31
|
Project Status |
Completed (Fiscal Year 2021)
|
Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
|
Keywords | 比較ゲノム解析 / ヒト胆道閉鎖症 / げっ歯類 / 疾患モデル / マウス / ラット / ヒト疾患モデル / 胆道閉鎖症 / 比較解析 / 胆管系発生 / 肝外胆管系 / シグナル経路 / 異種間比較 |
Outline of Final Research Achievements |
From the results of comparative genome analysis by in silico, we succeeded in creating Crisper/Cas9-deficient mice in the SOX17 promoter region conserved in rodents, and it became possible to analyze the cell-autonomous effect on gallbladder development. At present, gallbladder-specific upstream of SOX17 region has not been found, and the effect on the gallbladder epithelium in the surrounding environment (Mesenchymal system) remains an issue. Furthermore, in this study, as a result of comparing the pathology of the extrahepatic bile duct including the gallbladder in human Biliary atresia(BA) patients with the disease model mice, we found pathologies specific to SOX17-related BA, such as decreased expression of SOX17 in the gallbladder epithelium, increase in the peribiliary gland, and correlation between gallbladder shape and liver damage.
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Academic Significance and Societal Importance of the Research Achievements |
ヒトの胆道閉鎖症(BA)は、小児生体肝移植の70%を占める指定難病であるが、その病因や発症機序は未だ分かっていない。本研究では、ヒト患者においてSOX17が関連するBAの病態を明らかにしただけでなく、胆嚢の形態形成がどのようにBA発症に影響を与えるかを調査した初めての研究である。また、胆嚢を持たないラットと胆嚢を持つマウスの比較ゲノム解析を活用し、それらの進化的な意義を考察することで、学術的にも興味深い知見が得られた。今後、胆嚢上皮におけるSox17上流領域やその発現維持機構が解明されれば、ヒトや家畜のBAの治療や予防法の確立に繋がるだけでなく、動物種ごとの進化的な胆嚢の違いに迫れると考える。
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