Analysis of the role of UBD-dependent intracellular protein regulation in the pathogenesis of inflammatory bowel disease.

• Project/Area Number: 19K23990
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0903:Organ-based internal medicine and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kawamoto Ami 東京医科歯科大学, 医学部附属病院, 特任助教 (70849124)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); 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)
• Keywords: 炎症性腸疾患 / ユビキチン / UBD / Notch / 腸上皮細胞 / ヒト腸上皮 / TNF-α

Outline of Research at the Start

本研究では腸上皮における「UBD依存的ユビキチン様蛋白・プロテアソーム系(UBD依存的UBL-PSM系)」に着目し、同機構が制御する細胞内標的タンパクを探索・同定すると共に、炎症性腸疾患の発症等における機能的意義の解明を目指す。この為、ヒト腸上皮内「UBD依存的UBL-PSM系」標的分子の網羅的探索・同定 及びヒト腸上皮内「UBD依存的UBL-PSM系」の標的分子を介した機能の解析を実施する。

Outline of Final Research Achievements

Our present study regarding the newly identified intracellular proteolysis system, UBD-dependent UBL-PSM system, identified 62 candidate target proteins by iTRAQ analysis. Also, in addition to p62, two additional candidate target proteins of the UBL-PSM system were revealed by immunoprecipitation analysis. These findings suggest that UBD, a protein induced under an inflammatory environment in human intestinal epithelial cells, may exhibit its function through multiple target proteins.

Academic Significance and Societal Importance of the Research Achievements

今回の結果より、ヒト腸上皮細胞に於いて炎症環境で発現誘導される分子UBDは、複数の標的分子を有する可能性が示された。同標的分子群の蛋白分解制御を介し腸上皮機能を調節するという新たな炎症性腸疾患の病態の可能性も提示した。標的分子のさらなる探索等を通じ、炎症性腸疾患における「UBD依存的UBL-PSM系」の理解が一層進展し、新規治療法の開発につながることが期待できる。

Research Products

• [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] 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] Organoid-based regenerative medicine for inflammatory bowel diasease. (2020)
  • Author(s): Okamoto R, Shimizu H, Suzuki K, Kawamoto A, Takahashi J, Kawai M, Nagata S, Hiraguri Y, Takeoka S, Sugihara HY, Yui S, Watanabe M
  • Journal Title: Regen Ther. Volume: 13 Pages: 1-6
  • DOI: 10.1016/j.reth.2019.11.004
  • Peer Reviewed / Open Access