2019 Fiscal Year Final Research Report
Research investigating the onset mechanism of peroxisomal disease and the development of new biomarkers from lipid metabolomics
| Project/Area Number |
17K10062
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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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| Research Field |
Pediatrics
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| Research Institution | Teikyo University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Keywords | ペルオキシソーム病 / 先天代謝異常症 / 副腎白質ジストロフィー / 脂質メタボローム / リピトミクス / スフィンゴ糖脂質の網羅的解析 / アシルCoAの網羅的解析 / 分子種分析 |
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| Outline of Final Research Achievements |
An increase in the level of very long chain fatty acids (VLCFAs) was observed because of adrenoleukodystrophy, a peroxisomal disease, which is caused by a mutation in the ABCD1 gene. This study aimed to elucidate the onset mechanism and biomarkers of this disease from three perspectives. First, comprehensive molecular analysis systems were established for sphingomyelin and acyl-CoA, an intermediate of phospholipid synthesis. VLCFAs accumulated at the sn-1 position of phospholipids and levels of C26:1-CoA increased in the fibroblasts of patients. Second, several acyltransferases were identified as enzymes potentially responsible for the biosynthesis of VLCFA-containing phospholipids using ABCD1-deficient cells that were designed by gene editing. Third, the multichannel MRM analysis system for the comprehensive molecular analysis of glycosphingolipids was established using a chiral column and LC-MS.
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| Free Research Field |
生化学、分子生物学
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| Academic Significance and Societal Importance of the Research Achievements |
副腎白質ジストロフィーでは発症機構の解明と発症の前兆のバイオマーカーの発見が期待されている。本研究では従来十分な解析法がなかったスフィンゴミエリン、アシルCoA、スフィンゴ糖脂質について網羅的解析法を樹立したことで、新たに詳細なリピドミクスを行うことが可能となった。極長鎖脂肪酸をグリセロール１位に持つリン脂質やC26:1-CoAが顕著に蓄積することが明らかとなった。またリン脂質のグリセロール１位へ極長鎖脂肪酸を導入する酵素の解明が進んだ。これらにより病態の新たな一端が明らかとなり、発症の前兆となるバイオマーカーの発見の手筈も整ったといえる。臨床応用に向けてはさらなる研究の推進が必要である。
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