Generation of a molecular handle that modulates the strength of Notch signaling in vivo

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K22490
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: University of Shizuoka (2021); Nagoya University (2019-2020)
• Principal Investigator: Takeuchi Hideyuki 静岡県立大学, 薬学部, 教授 (80361608)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Keywords: 糖鎖 / O-グルコース糖鎖修飾 / 糖転移酵素 / Notchシグナル / 阻害剤

Outline of Final Research Achievements

The Notch signaling pathway is evolutionarily well conserved and plays an important role in determining cell fate in multicellular organisms. Disruption of Notch signaling is also involved in cancer development, malignant progression, and metastasis. Glycosylation at the extracellular domain of Notch plays an important role in its activation. Here we screened approximately 10,000 compounds against the protein O-glucosyltransferase 1 POGLUT1, and obtained about 50 compounds showing inhibitory activity against POGLUT1. During the research period, we contributed to the publication of 8 original papers and 3 review papers on the regulatory mechanism of Notch receptor function by glycosylation.

Free Research Field

糖鎖生物学

Academic Significance and Societal Importance of the Research Achievements

多細胞生物における細胞間シグナル伝達は、個体の恒常性を維持するために重要である。また、Notchシグナル伝達の異常によって病気になることも知られている。Notchシグナルは糖鎖修飾で制御される。本研究では、この糖鎖修飾を変化させる低分子化合物を探索し、グルコース転移酵素に対する阻害剤を見つけることに成功した。本成果は、がんなどのNotchシグナルの異常に起因する病気の治療に役立つ可能性がある。