Suppression of radiation-induced gastrointestinal disorders through the regulation of intestinal flora by the tumor suppressor p53
| Project/Area Number |
19K22525
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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 49:Pathology, infection/immunology, and related fields
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Project Period (FY) |
2019-06-28 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
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| Keywords | p53 / 腸内細菌叢 / 消化管障害 / microbiome |
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| Outline of Research at the Start |
p53はヒトがんの約半数で変異が生じる最も重要ながん抑制遺伝子である。p53ノックアウトマウスは放射線照射に対して重症の腸管症候群を示すことが知られているが、その機序はこれまで不明であった。我々は放射線照射前後のマウス糞便中のマイクロバイオーム解析の結果、p53が腸内細菌叢を制御することを発見した。本研究では、p53による腸内細菌叢制御に関わる標的遺伝子の探索、および腸内細菌の代謝産物解析を通じて、p53による消化管障害および消化器がん発症制御機構の解明を目指す。さらに標的遺伝子の多型と、消化器がんや炎症性消化管疾患の発症リスクとの関連も検討する。
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| Outline of Final Research Achievements |
p53 is the most frequently mutated tumor-suppressor that functions as a transcription factor. p53-deficient mice are sensitive to radiation-inducible gastrointestinal disorders, however its molecular mechanism has not been elucidated. We found a novel role of p53 in intestinal flora control. The gut microbiota and its metabolite, short-chain fatty acids, were altered in the feces of p53-deficient mice after irradiation. We screened the p53 target genes in the mouse small intestine and found that p53 strongly induces some acute phase proteins.
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| Academic Significance and Societal Importance of the Research Achievements |
近年の次世代シークエンス技術の進歩によりマイクロバイオーム研究は著しい発展を遂げ、腸内細菌叢の変化は肥満や炎症性腸疾患だけでなく、自閉症や肝がん、大腸がん等様々な疾患との関連が示されている。一方p53と腸内細菌叢の関連はこれまで報告されていなかった。本研究により、p53による腸内細菌叢の制御が明らかになったことで、消化器がん・炎症性腸疾患の新たな制御メカニズムが示唆された。さらに消化管障害に関与するp53下流遺伝子群は分泌タンパク質であることから、その投与により、高リスク群に対して腸内細菌叢やその代謝産物である短鎖脂肪酸を標的とした予防的介入または治療の可能性が開かれると期待される。
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Report
(3 results)
Research Products
(13 results)
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[Journal Article] Identification of a novel uterine leiomyoma GWAS locus in a Japanese population.2020
Author(s)
Sakai K, Tanikawa C, Hirasawa A, Terao C, Kamatani Y, Takahashi A, Momozawa Y, Hirata M, Kubo M, Wakai K, Matsuda K, et al.
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Journal Title
Scientific Reports
Volume: 10
Issue: 1
Pages: 1024-1024
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians2019
Author(s)
Lu Y, Kwcon SS, Cai Q, Tanikawa C, Shu XO, Jia WH, Xiang YB, Huyghe JR, Harrison TA, Kim J, Shin A, Kim DH, Matsuo K, Peters U, Matsuda K, Zheng W.
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Journal Title
Cancer Epidemiol Biomarkers Prev
Volume: 29
Pages: 477-486
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Identification of two novel breast cancer loci through large-scale genome-wide association study in the Japanese population2019
Author(s)
Low SK, Chin YM, Ito H, Matsuo K, Tanikawa C, Matsuda K, Saito H, Nakaya N, Shimizu A, Murakami Y, Inazawa J, Nakamura Y, Kubo M, Katagiri T, Miki Y.
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Journal Title
Sci Rep
Volume: 9
Pages: 17332-17332
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Large-Scale Genome-Wide Association Study of East Asians Identifies Loci Associated With Risk for Colorectal Cancer.2019
Author(s)
Lu Y, Kweon SS, Tanikawa C, Jia WH, Xiang YB, Cai Q, Zeng C, Schmit SL, Shin A, Matsuo K, Jee SH, Kim DH, Kim J, Wen W, Shi J, Guo X, Li B, Wang N, Zhang B, Li X, Shin MH, Li HL, Ren Z, Oh JH, Oze I, Ahn YO, Jung KJ, Conti DV, Schumacher FR, Rennert G, Je
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Journal Title
Gastroenterology
Volume: 156
Pages: 1455-1466
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
