| Project/Area Number |
18K08139
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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 53030:Respiratory medicine-related
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| Research Institution | University of Tsukuba |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | Has2 / 気管支喘息 / 高分子量ヒアルロン酸 / CD44 / TGF-β / IL-17 / HAS2 / TLR4 / マウス / 喘息 / COPD / 小胞体ストレス / Siglec-E / ヒアルロン酸 |
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| Outline of Final Research Achievements |
We previously reported that HAS2, which can generate high-molecular-weight hyaluronan (HMW-HA), is a novel candidate gene for determining susceptibility to adult asthma. However, little is known if HAS2 dysfunction affects eosinophilic airway inflammation. To answer this question, Ovalbumin (OVA) induced eosinophilic airway inflammation model was designed for Has2 heterozygous deficient (Has2+/－) mice and their wild-type (WT) littermates. The expression of Has2 mRNA was significantly decreased in OVA-stimulated Has2+/－ (Has2+/－-OVA) mice. Has2+/－-OVA mice also showed reduced mRNA expression for Cd44 and Tgfb1. Eosinophil counts, levels of various Th2 cytokines and chemokines in the BALF, and airway responsiveness were significantly increased in Has2+/－-OVA mice compared with OVA-treated WT mice. However, we didn't find the relationship between Has2 and Siglecs. Modulating HAS2 signaling might be a feasible treatment option for patients with intractable bronchial asthma.
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| Academic Significance and Societal Importance of the Research Achievements |
当研究室ではHAS2遺伝子が気管支喘息の疾患感受性遺伝子であることを独自に見出した。しかし、同遺伝子異常がどのように喘息病態形成に関与するかはこれまで明らかでなかった。本研究ではHas2遺伝子欠損マウスを用いることで、Has2遺伝子の異常が好酸球性気道炎症の増悪や気道過敏性の亢進をもたらすかどうか、およびSiglecの関与の有無を検証した。本研究によりHas2機能異常は急性好酸球性気道炎症の重症化をきたすこと。慢性好酸球性気道炎症や肺気腫形成モデルでも重症化することを発見した。本成果は喘息および他の炎症性肺疾患への新規治療アプローチの創出といった臨床応用へと展開する基盤となるものと期待される。
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