Challenging SASP control targeted on self-DNA.

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19419
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Takahashi Akiko 公益財団法人がん研究会, がん研究所 細胞老化研究部, 部長 (60380052)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: 細胞老化 / SASP / ゲノムDNA断片 / cGAS / 加齢性疾患

Outline of Final Research Achievements

In recent years, it has been revealed that senescent cells secrete various inflammatory proteins through a phenomenon known as SASP (senescence-associated secretory phenotype), which is implicated in the development of age-related diseases such as cancer, Alzheimer's disease, and COPD. Previous studies have shown that the activation of the cGAS/STING pathway by genomic DNA fragments leads to the induction of SASP. Therefore, the cGAS/STING pathway could be an important therapeutic target for controlling SASP in senescent cells. In this study, we conducted a screening of small molecules using the binding of cGAS to human genomic DNA fragments. We evaluated the inhibitory effect of hit compounds in human monocyte. In addition, we assessed the SASP inhibitory effects of candidate compounds in oncogene-induced senescent cells and identified novel compounds that can inhibit SASP.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

近年、細胞老化を起こした細胞を選択的に体内から除去しSASPを阻害することで、マウスの寿命が延長することや加齢性疾患の発症時期を遅らせることが報告されている。cGAS/STING経路を阻害することで有効なSASP制御法の開発が期待されるが、現在までに報告された阻害剤は全てインターフェロン応答を指標にして同定されたものであり、老化細胞におけるSASP阻害効果は不明である。本研究で同定された新規阻害化合物は、ヒトゲノム由来のDNAに対するcGASの結合を阻害することで、加齢性疾患の発症を阻害することのできる新規薬剤の開発に繋がることが期待される。