| Project/Area Number |
18K16288
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 55010:General surgery and pediatric surgery-related
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| Research Institution | Juntendo University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | CDH / pulmonary hypoplasia / Pbx1 / Meis1 / Runx1 / 先天性横隔膜ヘルニア / 肺低形成 / ナイトロフェン / 横隔膜 / 横隔膜ヘルニア症 |
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| Outline of Final Research Achievements |
Diaphragmatic and pulmonary gene expression levels of Pbx1, Meis1 and Runx1 were analyzed by qRT-PCR and protein expression was evaluated by immunofluorescence-double-staining.
In results, Relative mRNA expression of Pbx1, Meis1 and Runx1 was significantly decreased in developing diaphragms and lungs of nitrofen-exposed fetuses compared to controls. Confocal-laser-scanning-microscopy revealed markedly diminished Pbx1, Meis1 and Runx1 immunofluorescence in diaphragmatic and pulmonary mesenchyme, associated with less proliferating mesenchymal cells in nitrofen-exposed fetuses compared to controls.
In conclusions, decreased Pbx1, Meis1 and Runx1 expression during diaphragmatic development and lung branching morphogenesis may reduce mesenchymal cell proliferation, causing malformed PPFs and disrupted airway branching, thus leading to diaphragmatic defects and PH in the nitrofen-induced CDH model. These findings may therefore provide new insights into the pathomechanisms underlying CDH.
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| Academic Significance and Societal Importance of the Research Achievements |
先天性横隔膜ヘルニアの臨床的な致死率を鑑みるに、その発症機序を解明する研究は急務である。横隔膜欠損を引き起こす分子メカニズムの解明は、そのシグナル経路に対する治療的関与への可能性へと繋がるものである。
先天性横隔膜ヘルニア関連遺伝子の１つとされるPbx1、Meis1、Runx1が、ともに一連のシグナル経路を構成して、原始横隔膜の形成に大きな働きを担い、その破綻が疾患における横隔膜欠損の背景にあるというメカニズムを明らかにした。
この研究はヨーロッパで最も権威のある小児外科雑誌に掲載され、今後はさらにそこから胎児期における予防的投与薬剤の開発への重要な足がかりとなると確信している。
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