| 研究課題/領域番号 |
23K13858
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| 研究種目 |
若手研究
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| 配分区分 | 基金 |
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| 審査区分 |
小区分37030:ケミカルバイオロジー関連
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| 研究機関 | 国立研究開発法人理化学研究所 |
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研究代表者 |
Pham LienThiKim 国立研究開発法人理化学研究所, 環境資源科学研究センター, 特別研究員 (50865300)
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| 研究期間 (年度) |
2023-04-01 – 2026-03-31
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| 研究課題ステータス |
交付 (2023年度)
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| 配分額 *注記 |
4,680千円 (直接経費: 3,600千円、間接経費: 1,080千円)
2025年度: 1,430千円 (直接経費: 1,100千円、間接経費: 330千円)
2024年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円)
2023年度: 1,690千円 (直接経費: 1,300千円、間接経費: 390千円)
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| キーワード | SPT inhibitors / potent compounds / chemical-genomics |
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| 研究開始時の研究の概要 |
A direct inhibitor of Serine-palmitoyltransferase (SPT) will hold promise for future therapeutic studies. In this study, based on the yeast chemical-genomics screening data from thousands of bioactive compounds from the RIKEN Natural Product Depository and the University of Tokyo Drug Discovery Initiative Core Libraries, we focus on identifying new potent compounds that target SPT selectively.
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| 研究実績の概要 |
In the fiscal year 2023, we initially sifted through our database of over 6000 yeast chemical-genetic profiles to search for potential chemical compounds predicted to target SPT. We have identified three potential compounds, two of which exhibit conserved interactions across yeast and human cells, as determined by a genome-wide CRISPR-Cas9 human cell screening system. Drug-resistant mutants of one compound have been isolated, and analysis is underway.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
1: 当初の計画以上に進展している
理由
So far, we have achieved the planned aims, which include:
-Identification of potential yeast CG profiles and corresponding compounds: We have selected three compounds that demonstrate clear target prediction in SPT and the sphingolipid biosynthetic pathway.
-Conducting CG screening for potential compounds using HAP1 CRISPR/Cas9 screening: Two out of the three potential compounds have exhibited conserved targeting of SPT from yeast to human cells.
-Evaluation of cell growth bypassing SPT activity in rescue assays: This work is currently in progress.
-Isolation of Drug-Resistant Mutants in yeast: Spontaneous drug-resistant mutants of one compound have been selected and are undergoing analysis through genetic and next-generation sequencing to identify potential target genes.
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| 今後の研究の推進方策 |
In FY2024, our focus will persist on evaluating cell growth bypassing SPT activity in rescue assays, achieved by externally supplementing 3KS, DHS, and phytosphingosine (for yeast cells) or sphingosine (for human cells). Additionally, we will explore the other conditions involving the overexpression of SPT. We aim to complete the identification and confirmation of target genes through analyses of drug-resistant mutants. Furthermore, we will commence setting up LC-MS-based profiling of sphingolipids.
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