Elucidating the pathogenesis and discovering drugs for autoimmune diseases using patient-derived induced pluripotent stem cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16300
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: The University of Tokyo
• Principal Investigator: Natsumoto Bunki 東京大学, 医学部附属病院, 助教 (20837653)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 全身性エリテマトーデス / 自己免疫疾患 / Ⅰ型インターフェロン / 単球

Outline of Final Research Achievements

rs7197475-T has been reported as a risk SNP for systemic lupus erythematosus (SLE), and our eQTL (expression quantitative trait loci) analysis revealed that high expression of Gene Y in monocytes is associated with the risk. Gene Y has been reported to be involved in functions such as dsDNA repair, NFkB activation, and inhibition of apoptosis. We enforced the permanent overexpression of Gene Y in 293T and THP1 cells using lentiviral vectors. Upon stimulation with dsRNA or dsDNA, there was a significant increase in the production of type I IFN and TNF-alpha compared to the control. We are currently searching for therapeutic targets for SLE through RNA seq and drug screening.

Free Research Field

自己免疫疾患

Academic Significance and Societal Importance of the Research Achievements

本研究はOmics解析と生物学的実験を組み合わせることにより、SLEの病態の一端をin vitroに再現した。Gene YをレンチウイルスベクターでTHP1に恒久的に強制発現させ、dsRNAやdsDNAで刺激したところ、コントロールに比較しGene Y強制発現株において有意にⅠ型IFNやTNF-aの産生亢進が認められた。特にGene YとⅠ型IFNとの関連はこれまで報告されておらず、新規の発見となった。今後は刺激/未刺激サンプルのRNA-seqや薬剤スクリーニングを通してSLEの病態解明/治療ターゲットの検索を行っていく予定である。