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

2022 Fiscal Year Final Research Report

• 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
• Keywords: 炎症性腸疾患 / 接着分子 / インテグリン

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.

Free Research Field

炎症性腸疾患

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。