Developing Th17 differentiation regulators that target integrated stress response using chemical biology approaches

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K15415
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: The University of Tokushima
• Principal Investigator: HAMADA Yoshimasa 徳島大学, 先端酵素学研究所, 助教 (90805772)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 小胞体ストレス応答 / 統合的ストレス応答 / UPR / ISR / Th17細胞 / IL-17 / HTS

Outline of Final Research Achievements

There is a need to develop a therapeutic agent for IL-17 pathogenic diseases by inhibiting Th17 differentiation via integrated stress response (ISR) kinase. From HTS using ISR reporter cells, we identified Nigericin (Nig), which activates the ISR, and found that Nig activates OMA1-DELE1-HRI signaling by altering mitochondrial membrane potential. CD4+ T cells were extracted from mouse spleen and human blood, and differentiated into Th17. In the control group, IL-17 secretion was detected, but in the group co-treated with Nig during differentiation induction, IL-17 secretion was suppressed; in EAE pathology and psoriasis induction experiments, Nig improved the pathology.

Free Research Field

小胞体ストレス応答

Academic Significance and Societal Importance of the Research Achievements

北里大学の化合物ライブラリーをISR応答性レポーター細胞でスクリーニングし、低濃度で強力にISRを活性化できるNigを同定した。ヒト由来、マウス由来細胞のタンパク質レベルでもISRを活性化できたことから、高精度なISRレポーター、及び北里大学の化合物ライブラリーの有用性の学術的意義は大きい。北里大学天然化合物ライブラリーはノーベル賞を受賞した大村智先生が構築しており、スクリーニング用に広く提供されている。広範な研究分野で実績を上げており社会的な注目度も高い。今回の研究成果はISRがTh17関連疾患の標的になることを強く示唆しており、Th17関連疾患の治療薬、悪化予防薬への期待ができる。