Novel intestinal anti-inflammatory therapies by regulating adhesion molecule transport by the CUL3 ubiquitin ligase.

• Project/Area Number: 18K15822
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Nagoya City University
• Principal Investigator: ozeki Keiji 名古屋市立大学, 医薬学総合研究院(医学), 講師 (70750610)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 炎症性腸疾患 / 接着分子 / インテグリン / 細胞接着因子 / cullin3 / 難治性炎症性腸疾患 / Cullin3 / CUL3ユビキチンE3リガーゼタンパク質 / 血管内皮細胞 / BTB-ZnF ドメイン蛋白 / CUL3ユビキチンリガーゼ

Outline of Final Research Achievements

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. We investigated whether regulating the Cullin-3 (CUL3) ubiquitin (Ub)E3 ligase protein complex, a membrane transport regulator of cell adhesion factors, could be a new therapeutic strategy for UC treatment by targeting intracellular membrane transport of cell adhesion factors in vascular endothelial cells and leukaemic cells. E-selection, ICAM-1, ICAM-2, VCAM-1, MAdCAM-1 and integrin α- and β-chains under CUL3 gene knockdown in human umbilical vein endothelial cells (HUVEC) and human leukaemia cell lines, respectively, by Western blot (WB) method. Subcellular localisation analysis of integrin α- and β-chains by fluorescence immunostaining and protein level variation analysis using the Western blot (WB) method confirmed that the expression levels of integrin α- and β-chains were reduced, and then AlphaScreening was used to identify the responsible BTBP, but the appropriate target protein could not be identified.

Academic Significance and Societal Importance of the Research Achievements

現在本邦をはじめ潰瘍性大腸炎の患者は右肩上がりの増加を認めている。多くの新規のサイトカインや接着分子などリンパ球のトラフィッキングに関わる薬剤の新規開発が近年認められる。しかし、残念ながら今のところすべてを解決する治療法は確立されていない。今後も、既存治療効果を高め、更なる新規機序の薬剤開発の継続は必要だと考えられて今回の研究成果は今後の潰瘍性大腸炎の治療効果を高めていく可能性がある。

Research Products

• [Journal Article] Induction Therapy With a Combination of Weekly Adalimumab Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis in Patients With Ulcerative Colitis and Failure of Conventional Agents, Biologics and Janus Kinase Inhibitor (2023)
  • Author(s): Tanida S, Ozeki K, Katano T, Tanaka M, Shimura T, Kubota E, Kataoka H, Takahama T, Sasoh S, Kubota Y, Ban T, Ando T, Nakamura M, Joh T.
  • Journal Title: J Clin Med Res. Volume: 3 Issue: 3 Pages: 181-186
  • DOI: 10.14740/jocmr4887
  • Peer Reviewed / Open Access
• [Journal Article] Phase II Prospective Study of Trastuzumab in Combination with S-1 and Oxaliplatin (SOX100) Therapy for HER2-Positive Advanced Gastric Cancer (2022)
  • Author(s): Mori Y, Kataoka H, Ebi M, Adachi K, Yamaguchi Y, Hayashi N, Hirata Y, Sobue S, Ishihara R, Suzuki Y, Mizushima T, Inoue Y, Hasegawa I, Ono S, Hirano A, Kimura Y, Seno K, Ozeki K, Shimura T, Kubota E.
  • Journal Title: J Gastrointest Cancer Volume: 4 Issue: 4 Pages: 930-938
  • DOI: 10.1007/s12029-021-00711-0
  • Peer Reviewed / Open Access
• [Journal Article] Aseptic Abscess Syndrome With Ulcerative Colitis and Pyoderma Gangrenosum (2022)
  • Author(s): Ozeki K, Tanida S, Kataoka H.
  • Journal Title: Clin Gastroenterol Hepatol. Volume: 10 Issue: 10 Pages: 27-27
  • DOI: 10.1016/j.cgh.2022.04.040
  • Peer Reviewed / Open Access
• [Journal Article] 5-aminolaevulinic acid (5-ALA) accumulates in GIST-T1 cells and photodynamic diagnosis using 5-ALA identifies gastrointestinal stromal tumors (GISTs) in xenograft tumor models. (2021)
  • Author(s): Sasaki M, Tanaka M, Ichikawa H, Suzuki T, Nishie H, Ozeki K, Shimura T, Kubota E, Tanida S, Kataoka H
  • Journal Title: PLoS One Volume: 16 Issue: 4 Pages: e0249650-e0249650
  • DOI: 10.1371/journal.pone.0249650
  • Peer Reviewed / Open Access
• [Journal Article] Combination Therapy With Ustekinumab Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis in Patients With Refractory Ulcerative Colitis (2021)
  • Author(s): Tanida S, Ozeki K, Kanno T, Katano T, Sugimura N, Nishie H, Iwasaki H, Tanaka M, Shimura T, Kubota E, Kataoka H.
  • Journal Title: J Clin Med Res Volume: Nov;13(10-11) Issue: 10-11 Pages: 510-514
  • DOI: 10.14740/jocmr4625
  • Peer Reviewed / Open Access
• [Journal Article] Serum Exosomal Dicer Is a Useful Biomarker for Early Detection of Differentiated Gastric Adenocarcinoma (2020)
  • Author(s): Okuda Y, Shimura T, Iwasaki H, Katano T, Kitagawa M, Nishigaki R, Fukusada S, Natsume M, Tanaka M, Nishie H, Ozeki K, Yamada T, Kataoka H.
  • Journal Title: Digestion. Volume: Oct 13 Issue: 4 Pages: 1-10
  • DOI: 10.1159/000510993
  • Peer Reviewed / Open Access
• [Journal Article] Combination Therapy With Tofacitinib Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis as Induction Therapy for Refractory Ulcerative Colitis (2020)
  • Author(s): Tanida S, Ozeki K, Mizoshita T, Kitagawa M, Ozeki T, Tanaka M, Nishie H, Shimura T, Kubota E, Kataoka H.
  • Journal Title: J Clin Med Res. 2020 Volume: 1 Issue: 1 Pages: 36-40
  • DOI: 10.14740/jocmr4037
  • Peer Reviewed / Open Access
• [Journal Article] Combination Therapy With Tofacitinib Plus Intensive Granulocyte and Monocyte Adsorptive Apheresis as Induction Therapy for Refractory Ulcerative Colitis. (2020)
  • Author(s): Tanida S, Ozeki K, Mizoshita T, Kitagawa M, Ozeki T, Tanaka M, Nishie H, Shimura T, Kubota E, Kataoka H.
  • Journal Title: J Clin Med Res. Volume: 12(1) Pages: 36-40
  • Peer Reviewed / Open Access
• [Journal Article] Urinary Cysteine-Rich Protein 61 and Trefoil Factor 3 as Diagnostic Biomarkers for Colorectal Cancer. (2019)
  • Author(s): Shimura T, Iwasaki H, Kitagawa M, Ebi M, Yamada T, Yamada T, Katano T, Nisie H, Okamoto Y, Ozeki K, Mizoshita T, Kataoka H.
  • Journal Title: Transl Oncol. Volume: 12(3) Issue: 3 Pages: 539-544
  • DOI: 10.1016/j.tranon.2018.12.006
  • Peer Reviewed / Open Access
• [Journal Article] Combination Therapy With Intensive Granulocyte and Monocyte Adsorptive Apheresis Plus Ustekinumab in Patients With Refractory Crohn's Disease. (2018)
  • Author(s): Tanida S, Mizoshita T, Ozeki K, Katano T, Tanaka M, Nishie H, Shimura T, Okamoto Y, Kubota E, Kataoka H, Joh T.
  • Journal Title: Ther Apher Dial. Volume: 22 Issue: 3 Pages: 295-300
  • DOI: 10.1111/1744-9987.12697
  • Peer Reviewed