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研究生:伍家逸
研究生(外文):WU,JIA-YI
論文名稱:第二型轉麩胺酶在肺動脈內皮細胞功能調控所扮演之角色
論文名稱(外文):Tissue Transglutaminase Type 2 in the Regulation of Functions in Pulmonary Arterial Endothelial Cells
指導教授:吳懿哲賴宗聖賴宗聖引用關係
指導教授(外文):Wu,YIH-JERLAI,THUNG-SHEN
口試委員:葉宏一賴宗聖
口試委員(外文):YEH,-HUNG-ILAI,THUNG-SHEN
口試日期:2019-07-26
學位類別:碩士
校院名稱:馬偕醫學院
系所名稱:生物醫學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:中文
論文頁數:51
中文關鍵詞:肺動脈高壓轉麩胺酶肺動脈內皮細胞內皮素
外文關鍵詞:Pulmonary arterial hypertensionTransglutaminase type 2Pulmonary arterial endothelial cellEndothelin-1
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肺動脈高壓 (pulmonary arterial hypertension, PAH)是一種少見的慢性肺部血管疾病。雖然已有改善PAH預後的專一性療法,但其仍是一種高死亡率的嚴重疾病。目前治療PAH的藥物是藉由調控三個不同的訊息傳遞路徑,包括 一氧化氮(nitric oxide, NO), 前列腺環素(Prostacyclin, PGI2) 和內皮素(Endothelin 1, ET-1)。轉麩胺酶 (transglutaminase type2, TG2) 是ㄧ種多功能酵素,參與多種細胞內的訊息調控,包括細胞的生長、分化與附著。有文獻指出,TG2在許多慢性疾病中有顯著的表達,例如發炎疾病、組織纖維化、自體免疫與慢性退化性疾病。因此了解TG2在PAH中的分子機轉,將有助於開發治療PAH的藥物。本研究中,我們發現TG2 siRNA和TG2抑制劑會降低肺動脈內皮細胞(PAEC)的遷移能力。雖然已有文獻指出p38與內皮細胞的遷移能力有關,然而我們的數據表明TG2並不會藉由p38調控PAEC的遷移能力。另一方面,我們發現在PAEC中TG2 siRNA降低ET-1 mRNA和旁分泌的表現量。進一步地,我們發現在PAEC中TG2 siRNA抑制了c-Jun蛋白的磷酸化。最後,我們的實驗確定c-Jun抑制劑有效的降低PAEC的ET-1旁分泌表現量。綜合以上所述,我們相信TG2/c-Jun/AP1/ET-1訊息路徑可作為未來開發新藥的標的以及PAH預後的指標
Pulmonary arterial hypertension (PAH) is a progressive disease with an increased vascular resistance due to pulmonary arteriolar remodeling. Although precise pathogenesis of PAH remains unclear, three major pathways, including endothelin-1 (ET-1), nitric oxide (NO), and Prostacyclin (PGI2), closely related to pulmonary arterial endothelial cell (PAEC) dysfunction, are proven to be highly involved in PAH development. Transglutaminase type 2 (TG2) is a multifunction enzyme which catalyzes the transamination at the presence of calcium ion. Growing evidence suggests that TG2 are highly expressed in several chronic diseases, such as inflammation, tissue fibrosis, autoimmune diseases, and chronic degenerative disease. In addition, TG2 is also involved in many cell processes, including proliferation, differentiation and migration. Understanding the role of TG2 in PAH development may potentially help us develop the novel strategy of PAH therapy. In this study, we aimed at elucidation of whether TG2 regulates PAEC proliferation, migration, as well as paracrine functions including ET-1, NO and PGI2. We showed that TG2 inhibition significantly reduced PAEC migration, but not proliferation. More importantly, TG2 silencing was found to downregulate ET-1 mRNA expression and secretion into culture medium, without substantial alteration of NO and PGI2 secretion. Further looking into signaling pathways downstream to TG2, we found that TG2 silencing inhibited c-jun, but not c-fos, phosphorylation, and that the c-jun inhibitor significantly reduced ET-1 secretion. Taken together, this data suggests that TG2/c-jun/AP1/ET-1 is a novel pathway which may serve as a novel target for new drug development as well as novel biomarkers for PAH prognosis.
專有名詞縮寫對照表 4
圖索引 6
中文摘要 7
英文摘要 8
第一章 前言 10
1.1肺高壓 10
1.2肺動脈高壓 11
1.3組織轉麩胺酶 13
1.4轉麩胺酶在肺動脈高壓所扮演的角色 14
1.5本研究之重要性 15
第二章 材料與方法 17
2. 1材料 17
2. 1. 1材料清單 17
2. 1. 2儀器清單 19
2. 2方法 19
2. 2. 1培養人類肺動脈內皮細胞 19
2. 2. 2繼代人類肺動脈內皮細胞 20
2. 2. 3 TG2 siRNA 21
2. 2. 4 TG2 inhibitor (ERW1041E) 21
2. 2. 5 轉染TG2 siRNA 21
2. 2. 6核糖核酸分析 22
2. 2. 7蛋白質分析 23
2. 2. 8細胞功能分析 23
2. 2. 8. 1 細胞增殖分析 23
2. 2. 8. 2 細胞遷移測定 24
2. 2. 8. 3 血管新生測定 24
2. 2. 8. 4 旁分泌分析 24
第三章 實驗結果 25
3. 1 TG2 siRNA在PAEC中的抑制效果 25
3. 2 TG2表現對PAEC功能之影響 25
3. 2. 1增生能力 25
3. 2. 2遷移能力 26
3. 2. 3血管新生能力 26
3. 2. 4旁分泌能力 26
3. 2. 4. 1 NO 27
3. 2. 4. 2 PGI2 27
3. 2. 4. 3 ET-1 27
3. 3 TG2調控PAEC之ET-1表現之訊息傳導 28
3. 3. 1 p38 28
3. 3. 2 c-jun c-fos/AP-1 pathway 29
第四章 討論 44
第五章 結論 47
參考文獻 48



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