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研究生:賈志元
研究生(外文):Chih-Yuan Chia
論文名稱:熱休克蛋白90抑制劑AUY922對於發炎反應的免疫調控
論文名稱(外文):Immunomodulation of HSP90 inhibitor NVP-AUY922 on the inflammatory response
指導教授:呂思潔呂思潔引用關係
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:66
中文關鍵詞:熱休克蛋白90AUY922發炎反應巨噬細胞
外文關鍵詞:hsp90AUY922inflammatory responsemacrophage
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熱休克蛋白90是一種伴隨蛋白,經由與目標蛋白結合後幫助目標蛋白摺疊成正確的蛋白質結構,可以調控細胞週期、自我凋亡和訊息傳遞,這些都跟癌症有關,例如:細胞存活、增生、侵犯、轉移及血管新生,所以目前有多種Hsp90抑制物正在人體試驗,評估是否能治療癌症。本篇所研究的AUY922是一種熱休克蛋白90的抑制劑,會與熱休克蛋白90α上的ATP 結合位結合,以達到抑制的作用。已知AUY922可減低多種癌症腫瘤大小,例如:胃癌(gastric cancer)、多發性骨髓瘤(multiple myeloma)、乳癌(breast cancer)、前列腺癌(prostate cancer)及實質固態瘤(solid tumor)等,而AUY922正在人體試驗中被研究是否能治療這些癌症。
過去的文獻中指出熱休克蛋白90抑制劑會抑制發炎反應中的訊息傳遞因子,減少前發炎激素的表現量,藉此降低發炎反應。本篇利用PMA誘導THP-1細胞分化為巨噬細胞,再用LPS活化巨噬細胞,藉此觀察AUY922對巨噬細胞以及巨噬細胞活化過程的影響。我們使用沒有細胞毒性的AUY922濃度,在巨噬細胞及活化過程中發現,AUY922能有意義的減少前發炎激素IL-1β表現量,但不影響IL-8、IL-10、TNF-α的表現量,也會增加熱休克蛋白70表現量,但磷酸化的GSK-3(Ser21/9)則無明顯變化,也不會影響活性氧化物的表現量。在巨噬細胞活化的過程中,AUY922可以減少MMP-9的分泌量,但不會影響MMP-2的分泌量,也不會影響巨噬細胞的細胞表面分子。在敗血症小鼠模式中AUY922會減少IL-6、IL-10、IL-12p70、IFN-γ、MCP-1的表現量,也會減少體重下降的幅度。總之,AUY922在細胞及小鼠中都能減少發炎反應的產生。

Heat shock protein 90(Hsp90) is a kind of chaperone, binding client protein to help it to fold the correct protein structure. Hsp90 maintains cell cycle, apotosis and signal transduction. These are all about cancer, for example: cell viability, proliferation, invasion, migration and angiogenesis. Now, many Hsp90 inhibitors try to therapy cancer in clinical trial. In the study, AUY922 is the Hsp90 inhibitor and binds ATP-binding site of Hsp90α to inhibit Hsp90. It can decrease the size of tumor in many cancers, example: gastric cancer, multiple myeloma, breast cancer, prostate cancer and solid tumor. In previous study, Hsp90 inhibitor can inhibit signal transduction factor of inflammation and reduce expression of pro-inflammatory cytokine for decreasing inflammation. This study used PMA to induce THP-1 cell differentiation to macrophage, and then use lipopolysaccharide to induce macrophage activation. We observe the infleunce of AUY922 in PMA-induced macrophage and LPS-activated macrophage. We treat cells with non-cytotoxic concentration of AUY922 in this experiment. We found that AUY922 decreased expression of IL-1β, but no influence in expression of IL-8, IL-10, TNF-α in PMA-induced macrophage and LPS-activated macrophage. AUY922 increased expression of Hsp70, but no influence in expression of p-GSK-3(Ser21/9) and reactive oxygen species. In LPS- activated macrophage, AUY922 decreased expression of extracellular MMP-9 but not MMP-2. In sepsis mice model, AUY922 decrease expression of IL-6, IL-10, IL-12p70, IFN-γ, MCP-1 and range of mice weight decline. In conclusion, AUY922 may decrease inflammation in vitro and in vivo.

致謝 i
縮寫表 ii
目錄 iii
圖目錄 iv
表目錄 v
中文摘要 1
英文摘要 2
壹、 緒論 3
貳、 研究目標 8
參、 材料與方法 9
1、 常用溶液成分 9
2、 THP-1細胞 12
3、 THP-1細胞之培養 12
4、 以MTT assay 測量細胞存活率 13
5、 以酵素連結免疫吸附分析法(enzyme-linked immunosorbent assay,
ELISA) 測量細胞所分泌出的細胞激素含量 13
6、 以流式細胞儀分析細胞表面分子的表現量變化 14
7、 以gelatin zymography測量MMP-2/-9的胞外分泌量 14
8、 以H2DCF-DA測量細胞內活性氧化物的表現量 14
9、 以西方墨點法測量蛋白質表現量 15
10、 微珠免疫分析(Cytometric Bead Array, CBA)測量老鼠發炎細胞激素 16
11、 敗血症動物實驗模型(sepsis animal model) 16
12、 用LPS 誘導產生敗血症之動物模式 17
13、 統計方法 17
肆、 實驗結果 18
伍、 討論 33
陸、 圖表 35
柒、 參考文獻 57


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