3D intestinal development and carcinogenesis by Hippo-YAP pathway
| Project/Area Number |
19K08424
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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 53010:Gastroenterology-related
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| Research Institution | Yamaguchi University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
浅岡 洋一 山口大学, 大学院医学系研究科, 講師 (10436644)
清木 誠 山口大学, 大学院医学系研究科, 教授 (50226619)
柴田 健輔 山口大学, 大学院医学系研究科, 講師 (50529972)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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)
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| Keywords | YAP / Hippo / MAIT cell / Francisella tularensis / ribD / Hippo経路 / MST1/2 / MHC / サルモネラ / IL-8 / 感染免疫 / IL8 / 感染 / サイトカイン / 腸炎 |
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| Outline of Research at the Start |
転写共役因子YAPは炎症性腸炎や発癌の分子機構を制御し、有力な治療標的分子である。本研究では、ゲノム編集技術による各種遺伝子欠失細胞、ヒト腸オルガノイドなどの感染モデルでのサイトカイン産生、菌増殖・排除、抗原認識等の宿主―病原体相互作用と制御におけるYAPの役割、Hippo-YAPシグナル伝達経路による分子基盤ネットワークを解明し、腸炎、炎症病態さらには発がんの解明に繋げる。
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| Outline of Final Research Achievements |
Pathogenic roles of the altered metabolic programs against host immunity are poorly understood. Here, we show that a pathogenic strain Francisella tularensis subsp. tularensis (FT) has five amino acid substitutions of ribD in the riboflavin (RF) synthetic pathway; ribD is a converting enzyme responsible for generating metabolites recognized by mucosal associated invariant T (MAIT) cells. Metabolites from a free-living strain Francisella tularensis subsp. novicida (FN) activated MAIT cells in a T cell receptor (TCR)-dependent manner, whereas introduction of FT-type ribD to the free-living strain FN attenuated the activity in both humans and mice. Intranasal infection mouse model showed that the FT-type ribD-expressing FN impaired Th1-type MAIT cell expansion and bacterial clearance resulting in shortened survival compared to the free-living strain FN. These results demonstrate that Francisella tularensis acquires pathogenicity by alteration of metabolic programs during evolution.
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| Academic Significance and Societal Importance of the Research Achievements |
ヒト難治性疾患の病態解明と治療戦略の開拓を目指して研究を進めることができた。また、長年にわたり難病として未解明であった野兎病菌感染症において野兎病菌が宿主の免疫を逃れる機構として代謝のリプロラミングが寄与していることが判明し、難治性感染症の解明に貢献できた。
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Report
(4 results)
Research Products
(4 results)
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[Journal Article] In Staphylococcus aureus, the Particulate State of the Cell Envelope Is Required for the Efficient Induction of Host Defense Responses.2019
Author(s)
Kim B, Jiang T, Bae JH, Yun HS, Jang SH, Kim JH, Kim JD, Hur JH, Shibata K, Kurokawa K, Jung Y, Peschel A, Bae T, Lee BL.
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Journal Title
Infect Immun. 87(12). pii: e00674-19, 2019.
Volume: 87
Issue: 12
DOI
Related Report
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[Journal Article] The effect of MR1 ligand glycol-analogues on mucosal-associated invariant T (MAIT) cell activation.2019
Author(s)
Braganza, CD., Shibata, K., Fujiwara, A., Motozono, C., Sonoda, KH., Yamasaki, S., Stocker, BL., Timmer, MSM.
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Journal Title
Org Biomol Chem.
Volume: 17
Issue: 40
Pages: 8992-9000
DOI
Related Report
Peer Reviewed / Int'l Joint Research
