2022 Fiscal Year Final Research Report
Pathological analysys and new therapeutic development for inflammatory bowel diseaseon on the molecular basis of fluctuant activity of zinc-requiring enzyme
| Project/Area Number |
20K07056
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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 | Kyoto Pharmaceutical University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 亜鉛要求酵素 / 亜鉛不足による代謝変動 / 加齢による炎症応答変動 / 亜鉛輸送機構 / 腸アルカリホスファターゼ / 好中球浸潤 / 生命金属マーカー / γPGA-亜鉛錯体 |
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| Outline of Final Research Achievements |
Inflammatory bowel disease (IBD) model mice were produced by freely drinking water with 2% DSS using C57black/6J mice. As a candidate among new therapeutics, the γPGA-zinc complex was designed and synthesized for taking account of colon delivery after oral administration.
As age of mice, inflammation in colon of IBD mice was increased in comparison with control mice where plasma ALP activity was decreased, while IAP activity in colon was increased by migration of neutrophil into inflammation sites. From results for both age-dependent decrease of zinc amounts in colon and its more consumption by pathogenesis of IBD, the poly γ-glutamic acid (γPGA)-zinc complex was synthesized and examined to be daily administered by oral gavage to IBD model mice, and thus several symptoms of IBD were found to become clearly improved and cured after treatments. Therefore, it was concluded that the γPGA-zinc complex was proposed as a new candidate of therapeutic agent for treatment of IBD.
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| Free Research Field |
医薬品分析化学
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| Academic Significance and Societal Importance of the Research Achievements |
加齢に伴う代謝機能が炎症性腸疾患（IBD）の発症に関与する可能性を検証するため、標的分子として消化管の亜鉛要求酵素であるintestinal alkaline phosphatase（IAP）に注目した。加齢と共に消化管組織の亜鉛レベルが低下しIAP活性が低下するなら、上皮細胞から細胞外に漏出したATPや、腸内細菌から放出されたLPSがIAPによる分解を回避して管腔内を移動し大腸に集積することで炎症が発生する筈である。この作業仮説に基づいて、大腸送達性のポリγグルタミン酸-亜鉛錯体による治療効果を疾患モデルマウスで種々検討し、改善効果を見出した。本亜鉛錯体をIBDの治療薬候補として提案する。
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