Elucidation of the pathogenesis of endoplasmic reticulum stress in congenital neutropenia based on proteome analysis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15905
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Hiroshima University
• Principal Investigator: Mizoguchi Yoko 広島大学, 医系科学研究科(医), 助教 (30750533)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 先天性好中球減少症 / iPSC / UPR / 酸化ストレス

Outline of Final Research Achievements

Based on the hypothesis that decreased GSTP1 expression might be involved in the pathogenesis of CN, gene disruption of GSTP1 was performed using the CRISPR/Cas9 method in healthy-derived iPS cells. However, no differentiation defect was found. This indicates that a single deletion of GSTP1 alone does not affect neutrophil differentiation. For further analysis, we disrupted the ELANE gene using the CRISPR/Cas9 method in patient-derived iPS cells (CN-iPSC-NE KO) and examined whether the impairment of neutrophil differentiation was improved. CN-iPSC-NE KO showed an improved neutrophil differentiation defect. RNA-seq of CN-iPSC and CN-iPSC-NE KO-derived neutrophil progenitors revealed dysregulation of the antioxidant pathway in CN-iPSC. This suggests that not only UPR but also oxidative stress is involved in the pathogenesis of CN.

Free Research Field

小児血液・腫瘍

Academic Significance and Societal Importance of the Research Achievements

CNの病態にUPRのみならず酸化ストレスも関与している可能性が示唆され、薬剤スクリーニングを通して好中球分化障害を改善する分子を同定できれば、患者のQOLを改善する可能性がある。