Clarification of the cell-quality-control systems eliminating unhealthy cells from embryonic tissue and their dysregulation
| Project/Area Number |
20K21502
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 48:Biomedical structure and function and related fields
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| Research Institution | Osaka University |
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Principal Investigator |
Ishitani Tohru 大阪大学, 微生物病研究所, 教授 (40448428)
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| Project Period (FY) |
2020-07-30 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2021: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2020: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
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| Keywords | モザイク疾患 / 不良細胞 / ゼブラフィッシュ |
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| Outline of Research at the Start |
近年、ヒト胚では発生初期からランダムな遺伝子変異が頻繁に起きており、その変異により生じるモザイクが先天性疾患に関わることが明らかにされた。しかし、発生期に生じた変異がどのようなプロセスを経て疾患を引き起こすのかは不明である。一方で我々は最近、胚が変異細胞を除去するシステムを有することを発見しており、このシステムが変異モザイクの出現を抑制し、疾患を予防する能力があると推測している。そこで本研究では、モザイク疾患モデルゼブラフィッシュを作製・解析することでモザイク疾患と変異細胞除去機構の関係と、モザイク疾患の発症プロセスを分子・細胞・個体レベルで解明する。
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| Outline of Final Research Achievements |
We aimed to elucidate the relationship between mosaic disease and cell-quality-control system using zebrafish as a model. We succeeded to reveal that, in zebrafish larvae, neighboring normal cells sense precancerous cells and then induce senescence and physically push out these precancerous cells. In addition, in epithelia with p53 mutations or DNA damage, precancerous cells survive without being eliminated, and induce proliferation or secondary cellular senescence in adjacent normal cells to induce primary tumors.Thus,
we have clarified a new mechanism by which neighboring cells sense and eliminate defective cells during development. Furthermore, we have clarified that additional mutations and environmental factors suppress this elimination mechanism and drive disease development. Our results would provide a new understanding of the pathogenesis of human diseases.
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| Academic Significance and Societal Importance of the Research Achievements |
ゼブラフィッシュを用いたイメージング解析により、新たな疾患発症機構を明らかにした。これは、発生学のみならず医学においても重要な発見である。また、近年、動物愛護の考え方から哺乳類モデルを使った制限が徐々に制限され始めているが、本成果は非哺乳類モデルの医学研究における有用性を示す重要な成果と言える。
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Report
(4 results)
Research Products
(39 results)
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[Journal Article] Calcium sparks enhance the tissue fluidity within epithelial layers and promote apical extrusion of transformed cells2022
Author(s)
Kuromiya K, Aoki K, Ishibashi K, Yotabun M, Sekai M, Tanimura N, Iijima S, Ishikawa S, Kamasaki T, Akieda Y, Ishitani T, Hayashi T, Toda S, Yokoyama K, Lee CG, Usami I, Inoue H, Takigawa I, Gauquelin E, Sugimura K, Hino N, Fujita Y
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Journal Title
Cell Reports
Volume: 40
Issue: 2
Pages: 111078-111078
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Leucyl-tRNA synthetase deficiency systemically induces excessive autophagy in zebrafish.2021
Author(s)
Inoue M, Miyahara H, Shiraishi H, Shimizu N, Tsumori M, Kiyota K, Maeda M, Umeda R, Ishitani T, Hanada R, Ihara K, Hanada T.
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Journal Title
Sci Rep
Volume: 11
Issue: 1
Pages: 8392-8392
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] GNAO1 organizes the cytoskeletal remodeling and firing of developing neurons.2020
Author(s)
Akamine S, Okuzono S, Yamamoto H, Setoyama D, Sagata N, Ohgidani M, Kato TA, Ishitani T, Kato H, Masuda K, Matsushita Y, Ono H, Ishizaki Y, Sanefuji M, Saitsu H, Matsumoto N, Kang D, Kanba S, Nakabeppu Y, Sakai Y, Ohga S.
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Journal Title
FASEB J
Volume: 34
Issue: 12
Pages: 16601-16621
DOI
Related Report
Peer Reviewed / Open Access
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