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    題名: HDAC2及HDAC7媒介ET-1誘導人類肺纖維母細胞表現結締組織生長因子
    HDAC2 and HDAC7 mediate endothelin-1-induced CTGF expression in human lung fibroblasts
    作者: 花弘盛
    HUA, HUNG-SHENG
    貢獻者: 醫學科學研究所博士班
    林建煌
    陳炳常
    關鍵詞: 呼吸道纖維化;肺纖維母細胞;組蛋白去乙醯酶2;組蛋白去乙醯酶7;結締組織生長因子
    airway fibrosis;lung fibroblasts;HDAC2;HDAC7;CTGF
    日期: 2021-07-20
    上傳時間: 2022-03-14 22:46:18 (UTC+8)
    摘要: 已有研究指出抑制組蛋白去乙醯酶(HDACs)可改善動物模式誘發的肺纖維化。然而對於HDAC調控結締組織生長因子(CTGF)的機轉未詳。本研究探討了HDAC2及HDAC7在內皮素(ET-1)誘發肺纖維母細胞(WI-38)表現CTGF中的角色,同時也利用小鼠模型評估了卵白蛋白造成的呼吸道纖維化過程中HDAC2及HDAC7在肺部的表現量。在未受刺激時,HDAC2是一個內生性的CTGF抑制劑,在肺纖維母細胞中調控CTGF啟動子區域的H3去乙醯化。在ET-1刺激之下, HDAC2/Sin3A/MeCP2共抑制複合物被破壞並離開CTGF的啟動子區域,接著活化AP-1並啟動CTGF表現。同時,ET-1活化HDAC7並藉由p300來啟動AP-1轉錄活性,最終促進CTGF表現。總之在呼吸道纖維化過程中,HDAC2可能扮演保護性的角色,而HDAC7可能促進纖維化的發展進程。因此,促進HDAC2的活性及抑制HDAC7的活性具有潛力發展為治療呼吸道纖維化的新策略。
    Inhibition of histone deacetylases (HDACs) were revealed to attenuate lung fibrosis in animals. However, the roles of HDACs in the connective tissue growth factor (CTGF) synthesis are still unknown. The roles of HDAC2 and HDAC7 in endothelin (ET)-1-increased CTGF production in human lung fibroblast were investigated in this study. We also detected HDAC7 and HDAC2 protein level in ovalbumin (OVA)-caused airway fibrosis. Without stimulation, HDAC2 is an endogenous inhibitor of CTGF expression through regulation of H3 deacetylation on CTGF promoter in lung fibroblasts. With ET-1 stimulation, HDAC2/Sin3A/MeCP2 corepressor complex is disrupted and dissociated from CTGF promoter region followed by AP-1 activation and eventually initiates expression of CTGF. Meanwhile, ET-1 induced HDAC7 nuclear translocation to mediate AP-1 activation by recruiting p300 and then initiates CTGF expression. In conclusion, HDAC2 might play protective role in airway fibrosis and HDAC7 might promo the progression of airway fibrosis. Therefore, the promotion of HDAC2 activity and inhibition of HDAC7 activity have potential to be developed as novel therapeutic strategy in treatment of airway fibrosis.
    描述: 博士
    指導教授:林建煌
    指導教授:陳炳常
    委員:顏茂雄
    委員:黃聰龍
    委員:許銘仁
    資料類型: thesis
    顯示於類別:[醫學科學研究所] 博碩士論文

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