| Project/Area Number |
21K06552
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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 | Meijo University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
水本 秀二 名城大学, 薬学部, 准教授 (40443973)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | へパラン硫酸 / グリコサミノグリカン / 生合成 / 遺伝病 / ノックアウトマウス / 糖転移酵素 / EXTL3 / キシロース転移酵素 / ヘパラン硫酸 |
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| Outline of Research at the Start |
ヘパラン硫酸（HS）の生合成酵素遺伝子の変異に基づく遺伝病が発症する分子メカニズムを解明するために、変異型酵素タンパク質の解析、患者由来の不死化した細胞のHSと細胞内シグナル伝達系の解析、T細胞特異的ノックアウトマウスの解析、脳特異的ノックアウトマウスの解析を行う。さらに、異常となったHSを介した細胞内シグナル伝達系を改善する方法を模索し、本疾患の治療法の開発を目指す。
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| Outline of Final Research Achievements |
In this study, we have investigated the pathogenetic mechanisms of some genetic diseases caused by the mutations in glycosaminoglycan (GAG) biosynthetic enzymes. Their biochemical study had been limited. We have prepared a series of recombinant proteins with mutations reported to be presumable causes of such genetic diseases. The activities of recombinant enzymes were quantitively compared with those of wild-type proteins, and their reduction could be confirmed. In addition, immortalized cells were prepared from a patient with a genetic disease of a GAG biosynthetic enzyme, EXTL3. GAGs were purified from the cultured cells and their amount, disaccharide composition and chain length were analyzed. Compared with those from control subjects, they were significantly changed. We also generated three conditional knockout mice of EXTL3. T-cell-specific, brain-specific, and kidney-specific conditional knockout mice were obtained and effects on the corresponding organs were elucidated.
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| Academic Significance and Societal Importance of the Research Achievements |
グリコサミノグリカン生合成酵素遺伝子の変異に基づく遺伝病について、疾患発症の分子メカニズムを解明するために実験を行った。その詳細なメカニズムが解明できれば、本疾患の治療法の開発につながる。また、グリコサミノグリカン生合成酵素の欠損は、正常に機能していないシグナル伝達経路を補完するアゴニストの投与によって治療効果が現れる可能性があり、他の遺伝性疾患への波及効果も期待できる。
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