Establishment of granuloma formation model based on molecular response analysis

• Project/Area Number: 18K07934
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Oshima Shigeru 東京医科歯科大学, 医学部附属病院, 講師 (50376787)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: クローン病 / 肉芽腫 / オートファジー / p62 / ニッケル / LC3 / ユビキチン / 生命金属 / p62/SQSTM! / 腸炎

Outline of Final Research Achievements

Crohn's disease is an intractable disease of unknown cause and is characterized by the formation of granulomas in the intestinal tract and discontinuous lesions. We hypothesized that a foreign body (environmental factor) that can normally be eliminated could not be eliminated due to the genetic background of Crohn's disease, resulting in granulomas. Using foods and trace elements as foreign substances (environmental factors), we analyzed autophagy and tried to the establishment of granuloma formation model.

Academic Significance and Societal Importance of the Research Achievements

生体内に異物が入り込んだ際には防御反応として炎症や異物の排除が行われる。排除できない場合、異物を「隔離」によって最大の効果を得ようとする活動が肉芽腫形成である。この過程において重要なオートファジーと異物（環境因子）として食品・微量元素の関係を明らかにしたことは学術的に意義があり、予防医療への展開も考えられ、社会的に大きな意義のある成果を得た。

Research Products

• [Journal Article] Functional analysis of isoflavones using patient-derived human colonic organoids (2021)
  • Author(s): Tsuchiya Mao、Ito Go、Hama Minami、Nagata Sayaka、Kawamoto Ami、Suzuki Kohei、Shimizu Hiromichi、Anzai Sho、Takahashi Junichi、Kuno Reiko、Takeoka Sayaka、Hiraguri Yui、Sugihara Hady Yuki、Mizutani Tomohiro、Yui Shiro、Oshima Shigeru、Tsuchiya Kiichiro、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 542 Pages: 40-47
  • DOI: 10.1016/j.bbrc.2021.01.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Notch and TNF-α signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients (2021)
  • Author(s): Kuno Reiko、Ito Go、Kawamoto Ami、Hiraguri Yui、Sugihara Hady Yuki、Takeoka Sayaka、Nagata Sayaka、Takahashi Junichi、Tsuchiya Mao、Anzai Sho、Mizutani Tomohiro、Shimizu Hiromichi、Yui Shiro、Oshima Shigeru、Tsuchiya Kiichiro、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Biochemistry and Biophysics Reports Volume: 25 Pages: 100906-100906
  • DOI: 10.1016/j.bbrep.2020.100906
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intraepithelial Lymphocytes Suppress Intestinal Tumor Growth by Cell-to-Cell Contact via CD103/E-Cadherin Signal. (2021)
  • Author(s): Ryo Morikawa, Yasuhiro Nemoto, Yuki Yonemoto, Shohei Tanaka, Yuria Takei, Shigeru Oshima, Takashi Nagaishi, Kiichiro Tsuchiya, Kengo Nozaki , Tomohiro Mizutani, Tetsuya Nakamura, Mamoru Watanabe, Ryuichi Okamoto.
  • Journal Title: Cell Mol Gastroenterol Hepatol. Volume: 11 Issue: 5 Pages: 1483-1503
  • DOI: 10.1016/j.jcmgh.2021.01.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1 (2021)
  • Author(s): Daniel J Klionsky、Shu Aizawa、Amal Kamal Abdel-Aziz、Sara Abdelfatah、Mahmoud Abdellatif、Asghar Abdoli、Steffen Abel、Hagai Abeliovich、Marie H Abildgaard、Yakubu Princely Abudu、Abraham Acevedo-Arozena、Iannis E Adamopoulos、Khosrow Adeli、Timon E Adolph、Annagrazia Adornetto、Elma Aflaki、Galila Agam et al.
  • Journal Title: Autophagy Volume: 17 Issue: 1 Pages: 1-382
  • DOI: 10.1080/15548627.2020.1797280
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nickel ions attenuate autophagy flux and induce transglutaminase 2 (TG2) mediated post-translational modification of SQSTM1/p62. (2020)
  • Author(s): Emi Aonuma, Akiko Tamura, Hiroki Matsuda, Takehito Asakawa, Yuriko Sakamaki, Kana Otsubo, Yoichi Nibe, Michio Onizawa, Yasuhiro Nemoto, Takashi Nagaishi, Kiichiro Tsuchiya, Tetsuya Nakamura, Motohiro Uo, Mamoru Watanabe, Ryuichi Okamoto, Shigeru Oshima.
  • Journal Title: Biochem Biophys Res Commun. Volume: 542 Pages: 17-23
  • DOI: 10.1016/j.bbrc.2021.01.023
  • Peer Reviewed / Open Access
• [Journal Article] TGF-β promotes fetal gene expression and cell migration velocity in a wound repair model of untransformed intestinal epithelial cells (2020)
  • Author(s): Anzai Sho、Kawamoto Ami、Nagata Sayaka、Takahashi Junichi、Kawai Mao、Kuno Reiko、Kobayashi Sakurako、Watanabe Satoshi、Suzuki Kohei、Shimizu Hiromichi、Hiraguri Yui、Takeoka Sayaka、Sugihara Hady Yuki、Yui Shiro、Oshima Shigeru、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 524 Issue: 3 Pages: 533-541
  • DOI: 10.1016/j.bbrc.2020.01.108
  • Peer Reviewed
• [Journal Article] Receptor-Interacting Protein Kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells. (2020)
  • Author(s): Otsubo K, Maeyashiki C, Nibe Y, Tamura A, Aonuma E, Matsuda H, Kobayashi M, Onizawa M, Nemoto Y, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Torii S, Itakura E, Watanabe M, Oshima S.
  • Journal Title: FEBS letters Volume: 594 Issue: 10 Pages: 1586-1595
  • DOI: 10.1002/1873-3468.13748
  • Peer Reviewed / Open Access
• [Journal Article] CD8αα+ T cells show amoeboid shape and frequent morphological change in?vitro, and localize to small intestinal intraepithelial region in?vivo (2020)
  • Author(s): Takei Yuria、Nemoto Yasuhiro、Morikawa Ryo、Tanaka Shohei、Oshima Shigeru、Nagaishi Takashi、Okamoto Ryuichi、Tsuchiya Kiichiro、Nakamura Tetsuya、Watanabe Mamoru
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 523 Issue: 2 Pages: 328-335
  • DOI: 10.1016/j.bbrc.2019.12.021
  • Peer Reviewed / Open Access
• [Journal Article] High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage (2020)
  • Author(s): Tanaka Shohei、Nemoto Yasuhiro、Takei Yuria、Morikawa Ryo、Oshima Shigeru、Nagaishi Takashi、Okamoto Ryuichi、Tsuchiya Kiichiro、Nakamura Tetsuya、Stutte Susanne、Watanabe Mamoru
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 522 Issue: 4 Pages: 971-977
  • DOI: 10.1016/j.bbrc.2019.11.158
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic and environmental factors drive personalized medicine for Crohn’s disease (2018)
  • Author(s): Oshima Shigeru、Watanabe Mamoru
  • Journal Title: Journal of Clinical Investigation Volume: 128 Issue: 11 Pages: 4758-4760
  • DOI: 10.1172/jci124303
  • Peer Reviewed
• [Journal Article] Ubiquitin D is Upregulated by Synergy of Notch Signalling and TNF-α in the Inflamed Intestinal Epithelia of IBD Patients (2018)
  • Author(s): Kawamoto Ami、Nagata Sayaka、Anzai Sho、Takahashi Junichi、Kawai Mao、Hama Minami、Nogawa Daichi、Yamamoto Kouhei、Kuno Reiko、Suzuki Kohei、Shimizu Hiromichi、Hiraguri Yui、Yui Shiro、Oshima Shigeru、Tsuchiya Kiichiro、Nakamura Tetsuya、Ohtsuka Kazuo、Kitagawa Masanobu、Okamoto Ryuichi、Watanabe Mamoru
  • Journal Title: Journal of Crohn's and Colitis Volume: 13 Issue: 4 Pages: 495-509
  • DOI: 10.1093/ecco-jcc/jjy180
  • Peer Reviewed
• [Presentation] K33鎖ユビキチン鎖の機能解析 (2019)
  • Author(s): 大島 茂
  • Organizer: 新学術領域研究「ネオユビキチン」 令和元年度 第3回領域班会議
• [Presentation] ユビキチンコード遺伝子の大腸腫瘍における役割 (2019)
  • Author(s): 大島 茂、小林正典、田村皓子、松田浩紀、青沼映美、大坪加奈、仁部洋一、渡辺 守
  • Organizer: 第56回日本消化器免疫学会
• [Presentation] The role of ubiquitination in crosstalk of intestinal epithelial cell death and autophagic signaling was revealed by a novel polyubiquitin imaging system (2019)
  • Author(s): Kana Otsubo, Yoichi Nibe, Chiaki Maeyashiki, Akiko Tamura, Emi Aonuma, Hiroki Matsuda, Mamoru Watanabe, Shigeru Oshima
  • Organizer: 19th International congress of mucosal immunology
  • Int'l Joint Research
• [Presentation] K33-linked polyubiquitin is recruited by SQSTM1/p62 (2019)
  • Author(s): Shigeru Oshima, Yoichi Nibe, Akiko Tamura, Hiroki Matsuda, Emi Aonuma, Kana Otsubo, and Mamoru Watanabe.
  • Organizer: Keystone Symposia: Autophagy(B2)
  • Int'l Joint Research
• [Presentation] 非定型ユビキチン鎖の機能解明 (2019)
  • Author(s): 大島 茂
  • Organizer: 第１回新学術「ケモユビキチン」班会議・第２回ユビキチン研究会合同会議
• [Presentation] 独自ポリユビキチン鎖可視化技術を用いた新規腸炎調節分子の同定 (2018)
  • Author(s): 大島 茂、仁部洋一、松田浩紀、田村皓子、青沼映美、大坪加奈、渡辺 守
  • Organizer: 第55回日本消化器免疫学会総会
• [Presentation] 免疫疾患制御を目標としたユビキチン鎖可視化技術（PolyUb-FC）の開発 (2018)
  • Author(s): 大島 茂、仁部洋一、田村皓子、青沼映美、松田浩紀、大坪加奈、鬼澤道夫、渡辺 守
  • Organizer: 第46回日本臨床免疫学会総会