2023 Fiscal Year Final Research Report
Drug discovery against ER stress by using a novel luminescence probe sensing ER environments
| Project/Area Number |
20K06391
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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 42020:Veterinary medical science-related
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
Morimura Toshifumi 滋賀医科大学, 動物生命科学研究センター, 准教授 (20333338)
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| Co-Investigator(Kenkyū-buntansha) |
漆谷 真 滋賀医科大学, 医学部, 教授 (60332326)
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Keywords | ホタルルシフェラーゼ / 小胞体 / ミスフォールドタンパク質 / diosmetin |
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| Outline of Final Research Achievements |
Accumulation of misfolded proteins in the endoplasmic reticulum (ER) is involved in numerous disorders. I demonstrate that firefly luciferase (FL) fused with an ER penetration signal is misfolded and accumulates in the ER, evoking ER stress. FL activity in the ER was increased by the N-glycosylation inhibitor tunicamycin, in a site dependent manner. The ER calcium pump inhibitor thapsigargin and reductant dithiothreitol, both known disrupters of ER protein folding, also enhanced luminal FL activity in the absence of newly translation. Screening of dietary ingredients uncovered that several flavones including apigenin and diosmetin were able to induce luminal FL activity. These compounds enhanced extracellular release of luminal FL, and diosmetin significantly increased ER exit of a disease-associated misfolded membrane protein from the ER. These results indicate that luminal FL can be utilized to identify compounds that can improve the conformation of luminal misfolded proteins.
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| Free Research Field |
神経科学
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| Academic Significance and Societal Importance of the Research Achievements |
小胞体内のミスフォールドタンパク質の蓄積が関与する疾患は、遺伝性疾患から生活習慣病に至るまで幅広く、ミスフォールドを改善する化合物の検索は医療上重要な位置を占めている。本研究より、感度が高く定量性に優れた小胞体内のホタルルシフェラーゼが、小胞体内のミスフォールドタンパク質の構造を改善する化合物の検索に有効である事が示され、これまでに見出せなかった抗小胞体ストレス化合物の発見につながる事が期待できる。今回候補薬として同定されたdiosmetinは、細胞質のミスフォールドタンパク質に対する構造改善化合物としても報告されており、小胞体ストレスが関与する疾患への治療応用に期待が持てる。
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