| Project/Area Number |
21K07971
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Kawasaki Medical School |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | RNA結合蛋白質 / 食道扁平上皮癌 / 転写後調節機構 / 食道扁平上皮がん / TIA1 |
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| Outline of Research at the Start |
本研究は、RNA結合蛋白質TIA1aが食道癌の進展を促進する分子機構の全容を解明し、これを標的とした特異性の高い新たな治療戦略開発を目指す。 TIA1aが食道癌特異的に高発現するメカニズムの解析や、 高発現したTIA1aの細胞内局在変化を制御する因子の同定を行い、TIA1aの食道癌特異的な発現・機能調節に関わる分子マップを完成する。さらに TIA1aを中心とした分子ネットワークを広範囲に制御する特異的介入法の検討を行い、TIA1aを標的とする治療が及ぼす効果を明らかにする。
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| Outline of Final Research Achievements |
We focused on the alternative splicing control mechanism of the TIA1 gene and the phosphorylation regulators of TIA1a during the pathogenesis of esophageal squamous cell carcinoma (ESCC). We predicted multiple phosphorylation kinases based on the amino acid sequence of TIA1a and identified a kinase (kinase2: lab name) that controls the intracellular localization of TIA1a. In addition, a splicing factor (SF-X: lab name) that could induce TIA1a-type splicing was identified by knockdown experiments. Specific siRNAs and inhibitors against these identified factors significantly suppressed the cell growth of ESCC cells. RNA-seq data analysis confirmed that TIA1a, kinase2, and SF-X expression levels increased dramatically in ESCC tissues compared to normal tissues. Moreover, there was a positive correlation between TIA1a levels, kinase2 levels, and SF-X levels. These results suggest that the identified factors could be novel therapeutic targets for ESCC.
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| Academic Significance and Societal Importance of the Research Achievements |
RBPは正常細胞でも様々な生理機能を担っており、発現量制御に着目した従来の治療戦略では重大な副作用が予測される。本研究の成果をモデルに、RBPが癌細胞の悪性形質獲得のために必要な機能モジュール群のみを調節する分子機構の全貌を解明し、これを可逆的にON/OFFすることでこの機能モジュール全体を特異的に調節できれば、有効な分子標的治療薬の少ないESCCにおいて、腫瘍や特定の悪性形質に選択性が高い治療法開発が可能になる。
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