| Project/Area Number |
17K16123
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Neurology
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| Research Institution | Wakayama Medical University (2018)
The University of Tokushima (2017) |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | アミロイド / アミロイドーシス / ヘパラン硫酸 / グリコサミノグリカン / 細胞外糖鎖 / トランスサイレチン / 細胞外硫酸化糖鎖 |
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| Outline of Final Research Achievements |
The highly sulfated domains of heparan sulfate (HS), also known as HS S-domains, concsist of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)] and are selectively remodeled by extracellular endoglucosamine 6-sulfatases (Sulfs). Although HS S-domains are critical for signal transduction of several growth factors, their roles in amyloidoses are not yet fully understood. Here, we found HS S-domains in the kidney of a patient with transthyretin amyloidosis. In in vitro assays, heparin, a structural analog of HS S-domains, promoted aggregation of transthyretin in an HS S-domain-dependent manner. Interactions of cells with transthyretin fibrils and cytotoxicity of these fibrils depended on HS S-domains. Glypican-5, encoded by the susceptibility gene for nephrotic syndrome GPC5, was found to be accumulated in the transthyretin amyloidosis kidney. Thus, we propose that HS S-domains can be a novel therapeutic targets of transthyretin amyloidosis.
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| Academic Significance and Societal Importance of the Research Achievements |
ATTRアミロイドーシスは日本国内にも患者の集積地が存在する難治性の疾患である。本失火には肝移植の有効性が確立されてはいるが、ドナー不足、患者やドナーに対する精神・肉体的な負担、移植後のアミロイドーシス進行といった問題、病気の進行や年齢等の理由により約8割の患者は移植手術の適用とならない。従ってより一般的かつ侵襲性の低い新たな治療方法の開発が必要である。本研究により、ヘパラン硫酸多硫酸化ドメインがTTR線維の形成や細胞毒性の発揮に重要であることが分かり、ヘパラン硫酸多硫酸化ドメインを選択的に酵素分解することによりATTRアミロイドーシス病態を制御する新たな治療戦略が示唆された。
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