2020 Fiscal Year Final Research Report
Investigetion of the pathomechanisims of smoking-related lung disease focusing on tissue stem cell niche
| Project/Area Number |
18K08179
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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 | University of Miyazaki |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
松尾 彩子 宮崎大学, 医学部, 医員 (40776332)
坪内 拡伸 宮崎大学, 医学部, 助教 (60573988)
松元 信弘 宮崎大学, 医学部, 助教 (70418838)
三浦 綾子 宮崎大学, 医学部, 助教 (70710903)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | 肺微小環境 / 細胞老化 |
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| Outline of Final Research Achievements |
We investigated the role of Pten, a tumor suppressor, in alveolar type 2 (AT2). AT2-specific Pten null mice spontaneously developed age-related emphysema. AT2-specific Pten null mice showed decreased numbers of AT2 and increased numbers of lung mesenchymal cells (LMSc) 8 weeks after tamoxifen treatment. RNA sequencing of isolated AT2 and LMSc identified the perturbation of epithelial-mesenchymal interaction signaling. Deletion of Pten in AT2 increased the number of senescent AT2. Lung epithelial cell-specific Pten deficiency provoked accumulation of dysmorphic and dysfunctional mitochondria with increased reactive oxygen species production. Moreover, lung epithelial cell-specific Pten deletion induced excessive senescence-associated secretory phenotype. Our results highlight that Pten in AT2 has an essential role in controlling age-related emphysema by regulating cellular senescence and epithelial-mesenchymal and mitochondrial homeostasis.
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| Free Research Field |
呼吸器内科
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| Academic Significance and Societal Importance of the Research Achievements |
慢性閉塞性肺疾患と特発性肺線維症は原因不明の線維性疾患であり、進行性の呼吸不全を来す。両疾患ともに有効な薬物療法がない。本研究は、組織幹細胞ニッチの恒常性を制御する分子メカニズムを解明するもので、難治性呼吸器疾患の病態機構の理解と新規治療法を樹立する上で極めて重要である。組織幹細胞ニッチ破綻に着目した慢性閉塞性肺疾患と特発性肺線維症の病態解明は新規のアイデアである。慢性閉塞性肺疾患と特発性肺線維症の病態解析と新規治療法の樹立を目指す本研究の達成は呼吸器医療に計り知れない貢献をもたらす。組織幹細胞ニッチ機構の理解は、多臓器のリモデリング疾患や発癌機構の理解を飛躍的に前進させる。
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