Constructing a molecular basis for regulation of colonic mucus production and drug discovery

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07456
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Himeji Dokkyo University
• Principal Investigator: NAGAKUBO Daisuke 姫路獨協大学, 薬学部, 教授 (10368293)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 大腸 / 杯細胞 / 粘液 / ケモカイン / 上皮間葉転換

Outline of Final Research Achievements

The large intestine contains two layers of mucus composed of glycoprotein mucin, which prevents bacteria from entering the host. Goblet cells in the colonic epithelium are responsible for the production of mucus. In this research project, we analyzed the differentiation and regulation of mucus production of goblet cells. As a result, we clarified the possibility that the chemokine CCL28, expressed in the large intestine, induces differentiation into goblet cells via its receptor CCR10 and promotes mucus production of goblet cells. Furthermore, from the analysis of the effects of chemokines on colorectal epithelial cells, we found that inhibition of another CCL28 receptor, CCR3, induces epithelial-mesenchymal transition and formation of polyploid giant cells, which are involved in cancer malignant transformation, and clarified its signal transduction pathway.

Free Research Field

実験病理学、生化学、免疫学

Academic Significance and Societal Importance of the Research Achievements

大腸には膨大な数の細菌が存在するにも関わらず、宿主との共生関係が成立している。そこには大腸上皮の中の杯細胞と呼ばれる細胞が分泌する粘液が重要な役割を果たしている。本研究は、液性因子であるケモカインCCL28が大腸における杯細胞の分化や粘液産生を制御するという新規の概念を提供した。また、CCL28の受容体でもあるCCR3の阻害は大腸がんの悪性化の誘導にも関わることを明らかにした。今回得られた分子機構は新規の知見であり、それらが杯細胞の機能異常による炎症性腸疾患、あるいは大腸がんなどに対する将来的な創薬の治療標的に繋がることが期待される。