Physiological role of CFTR interaction receptor under sterile inflammatory response in cystic fibrosis

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16508
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Kwansei Gakuin University
• Principal Investigator: Fukuda Ryosuke 関西学院大学, 理工学部, 助教 (90825308)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 呼吸器炎症 / 上皮細胞炎症応答 / 嚢胞性線維症 / CFTR

Outline of Final Research Achievements

This research has been shown that activation of EPHA2 ligand-independent signaling associated with CFTR expression abnormalities are involved in the development of sterile airway inflammation in cystic fibrosis (CF). Constitutive expression of functional CFTR facilitates binding of EPHA2 and its ligand EFNA1 and attenuates EPHA2 ligand-independent pathways dependent inflammation during air-liquid interface culturing in CFBE cells. EPHA2 ligand-independent pathways and downstream ERK signaling pathways inhibition showed the effect of suppressing sterile inflammation in primary cultured airway epithelial cells derived from CF patients. These results suggest that usefulness of the EPHA2 pathway as a therapeutic target for chronic inflammation in the early stage of CF and also in the CFTR-deficiency associated disease such as COPD.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

呼吸器慢性炎症はCF病態増悪の根本的な原因であり, EPHA2は病態進行を遅延させる治療法の有用な治療標的になり得る. またCFTR機能異常はCFのみならず感染性呼吸器疾患やCOPDにおいても報告されており, 種々の呼吸器炎症病態に本課題で見出された機構が関与している可能性がある. 今後, EPHA2を標的とした炎症抑制薬の評価を行なうことで, 様々な呼吸器炎症における有効性を明らかにできると考える. また, 本課題中に開発したEPH-EFN結合性評価法を応用することで網羅的な生細胞での結合試験法の確立にも至り, 幅広い疾患におけるEPH受容体の重要性を議論するための基盤構築も成し得た.