2023 Fiscal Year Final Research Report
TRNT1 functional analysis for the Pathological Understanding of SIFD
| Project/Area Number |
21K07836
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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 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Asahikawa Medical College |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
吉田 陽一郎 旭川医科大学, 大学病院, 助教 (80750306)
石羽澤 映美 旭川医科大学, 大学病院, 病院助教 (90516402)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | SIFD / TRNT1 / 小胞体ストレス |
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| Outline of Final Research Achievements |
During study period, the following findings were made:
1. In PBMC of the patient, TRNT1 was expressed at a lower level than in healthy individuals, even though it was the same size.This was due to its constant degradation by the proteasome because of its instability.2.Patient fibroblasts exhibited increased drug-induced endoplasmic reticulum (ER) stress compared to healthy fibroblasts.3.TRNT1 siRNA knockdown in immortalized fibroblasts also showed increased ER stress, which was alleviated by the chemical chaperone 4-phenylbutyric acid. 4.When TRNT1 was knocked down in mouse macrophage-like Raw cells, there was an increase in TNF production and NF-kB signaling.
From the above, it was suggested that in SIFD (Sideroblastic Anemia with B-cell Immunodeficiency, Periodic Fevers, and Developmental Delay), enhanced ER stress response occurs, which is likely involved in the pathogenesis of the disease.
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| Free Research Field |
小児科学
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| Academic Significance and Societal Importance of the Research Achievements |
SIFDは最近発見された希少疾患であり、病態の解明が十分になされていない。本研究でTRNT1機能低下を示す異なる条件で共通して見られた小胞体ストレス亢進は、tRNAアミノアシル化に係る酵素の機能喪失の結果を詳細解明する点で学術的な意義があるのはもちろんだが、本疾患は臨床的に35%が早期死亡する予後不良の疾患である。骨髄移植は合併症により成績も悪く、現状は多彩な症候に対する対症療法を行うしか解決方法は無い。しかし本研究の知見は、ケミカルシャペロン作用のある薬剤を投与する事で、病気の進行を抑制できる可能性を示している。明らかに新規治療法開発に貢献する知見である。
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