Elucidation of the regulation mechanism of cystic fibrosis-specific splice variant expression and development of novel therapeutic strategies

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07114
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Sojo University
• Principal Investigator: Shuto Keiko 崇城大学, 薬学部, 講師 (70510692)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 嚢胞性線維症 / SIGIRR / スプライスバリアント / IL-37 / 化合物探索

Outline of Final Research Achievements

Cystic Fibrosis (CF) is a hereditary disorder typically characterized by infection-associated chronic lung inflammation. Toll-like receptors (TLRs) are innate immune receptors that sense pathogen-associated molecular patterns (PAMPs) and their excessive or prolonged activation is considered as one of the mechanisms for CF hyperinflammatory phenotype. SIGIRR is a transmembrane protein acting as a negative regulator of multiple TLR signaling pathways after stimulation with anti-inflammatory cytokine IL-37, a ligand for SIGIRR.
We have recently demonstrated the defective surface expression of full-length SIGIRR (WT-SIGIRR) in CF airway epithelial cells due to its splicing variant Δ8-SIGIRR, suggesting impaired IL-37-depdendent anti-inflammatory activity.
In order to restore its surface expression in CF cells, we performed screening analysis and revealed that factor X inhibitor is a specific inducer for WT-SIGIRR.

Free Research Field

細胞生物学、薬理学

Academic Significance and Societal Importance of the Research Achievements

CF気道上皮細胞おいて分子X阻害剤によりWT-SIGIRRを特異的に発現誘導する事は、分子X family阻害剤が持つ細胞毒性等の副作用を軽減しながらIL-37による抗炎症作用を回復させる為に有用である可能性が示唆された。
本知見は、抗炎症分子SIGIRRを強力に発現誘導する標的を明らかにした初めての報告であり、CF気道炎症に対する新たな治療戦略を提起するものである。