Exploring the Molecular Pathogenesis of Pulmonary Alveolar Microlithiasis and Developing Novel Therapeutic Approaches Using Integrated Omics Analysis
| Project/Area Number |
20K08521
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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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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
SAITO ATSUSHI 札幌医科大学, 医学部, 講師 (00768939)
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| Co-Investigator(Kenkyū-buntansha) |
藤谷 直樹 札幌医科大学, 医学部, 助教 (10374191)
高宮 里奈 東京大学, 大学院医学系研究科(医学部), 特任助教 (70365419)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 肺胞微石症 / リン酸トランスポーター / 希少肺疾患 / オミクス解析 / 治療法開発 / 動物実験モデル / ナトリウムリン酸共輸送体 / 肺胞マクロファージ |
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| Outline of Research at the Start |
肺胞微石症はSLC34A2遺伝子変異が原因で肺胞内にリン酸カルシウム結石を生じる希少肺疾患です。現在まで有効な治療法はなく、その開発が急務である。同疾患モデルマウスを用いた解析で、低リン食治療が進行抑制・病勢の改善が確認されていますが、低リン食治療は軽微ながら栄養障害が原因と考えられる体重減少の副作用もあることから、臨床応用へはさらなる改善が望まれ本研究でさらに研究を進める予定です。これまでの研究結果と合わせて臨床応用への橋渡しが期待されます。
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| Outline of Final Research Achievements |
PAM is a rare autosomal recessive lung disorder caused by genetic abnormalities in the Npt2b, leading to the formation of calcium phosphate stones within the alveolar spaces. Through pathogenesis analysis using a PAM mouse model, it was observed that intrapulmonary administration of clodronate liposomes increased microlith accumulation, suggesting the involvement of alveolar macrophages in microlith removal from the alveoli. Furthermore, lipidomics analysis revealed significant elevation of arachidonic acid and other eicosanoids, as well as COX-2. It was found that downstream signaling molecules such as PGE2 and LXA4, which are anti-inflammatory mediators, were significantly increased, indicating their role in suppressing inflammation in the lungs associated with microlith formation. Additionally, COX-2 expression was significantly decreased with the previously reported therapy involving phosphate-binding agents, reaffirming the effectiveness of this treatment approach.
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| Academic Significance and Societal Importance of the Research Achievements |
肺胞微石症のような超希少疾患は対象患者が少ないこともあり、研究者も少なく病態解明がなかなか進まないことが多い。本研究ではマウスモデルを用いることで新たに病態解明を進めることができた。本研究の結果は今後臨床応用されることで本疾患に苦しむ患者に対する希望となると考える。
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Report
(4 results)
Research Products
(18 results)
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[Journal Article] N-glycosylation regulates MET processing and signaling2022
Author(s)
Atsushi Saitou, Yoshihiro Hasegawa, Naoki Fujitani, Shigeru Ariki, Yasuaki Uehara, Ukichiro Hashimoto, Atsushi Saito, Koji Kuronuma, Kunio Matsumoto, Hirofumi Chiba, Motoko Takahashi
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Journal Title
Cancer Science
Volume: ー
Issue: 4
Pages: 1292-1304
DOI
Related Report
Peer Reviewed / Open Access
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