2022 Fiscal Year Final Research Report
Sulfated polysacharides exert biphasic regulations on inflammation and allergic skin diseases: roles of polysaccharide degradation
| Project/Area Number |
19K07091
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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 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | Hoshi University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
小宮根 真弓 自治医科大学, 医学部, 教授 (00282632)
東 恭平 東京理科大学, 薬学部薬学科, 准教授 (10463829)
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| Project Period (FY) |
2019-04-01 – 2023-03-31
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| Keywords | アレルギー性皮膚炎 / ヘパラナーゼ / 炎症 / 細胞外マトリックス / 基底膜 / ヒアルロン酸 / コンドロイチン硫酸 / フラグメント分子軌道法 |
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| Outline of Final Research Achievements |
The number of patients with allergic skin inflammation such as atopic dermatitis is estimated to be over 400,000. To ameliorate our understanding on the pathogenesis of atopic dermatitis, we focused on involvement of heparanase in the dermatitis. Heparanase expression was detected in the atopic dermatitis skins. Novel heparanase inhibitors were explored, focusing on chondroitin sulfate and hyaluronic acid that are present in the body. These polysaccharides were sulfated using the chemical modification technique. These sulfated polysaccharides exerted stronger heparanase inhibitory activity than heparin. They were able to suppress heparanase-dependent inflammatory events at the cellular level. In order to clarify molecular basis of the inhibitory effect, fragment molecular orbital method was applied. Interaction between sulfated polysaccharides and basic amino acid residues on heparanase protein, especially those in heparin-binding domain I is involved in the inhibitory activity.
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| Free Research Field |
生化学
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| Academic Significance and Societal Importance of the Research Achievements |
ヘパラナーゼなどの糖鎖切断酵素によって新たに産生される糖鎖断片、また人為的に硫酸化などの化学修飾を行った糖鎖が起炎症活性・抗炎症活性を有する場合が示され、この手法による新たな生理活性物質の探索の可能性を示した。抗炎症活性のうちヘパラナーゼの酵素活性阻害作用に着目すると、この機能に特化した高硫酸化コンドロイチン硫酸、硫酸化ヒアルロン酸という硫酸化糖鎖を新たに見出し、その構造的基盤を解明することに成功した。本研究の成果により、アトピー性皮膚炎などの炎症性疾患に対して、ヘパラナーゼの阻害効果を通じて炎症を鎮静化する新たな阻害剤の提案をすることができた。
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