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標題: | 內質網蛋白 TXNDC5(硫氧還蛋白 5)在肺纖維化的角色 The Role of ER-Resident Protein TXNDC5 in Pulmonary Fibrosis |
作者: | Ying Tung Lee 李尹彤 |
指導教授: | 楊鎧鍵(Kai-Chien Yang) |
關鍵字: | 肺纖維化,TXNDC5 (硫氧還蛋白5),TGF-β1 (轉化生長因子-β),bleomycin,內質網壓力, pulmonary fibrosis,Thioredoxin Domain Containing 5 (TXNDC5),endoplasmic reticulum stress (ER stress),TGF β1,bleomycin, |
出版年 : | 2017 |
學位: | 碩士 |
摘要: | 肺纖維化 (pulmonary fibrosis) 是肺組纖產生嚴重結痂變化,可以是原發性或次發於其他肺部或系統性疾病。肺纖維化的形成,始於肺組織中的纖維母細胞 (fibroblast) 因受到各種化學性或物理性刺激時,被活化而增生,並持續分泌細胞外間質(extracellular matrix)如膠原蛋白 (Collagen),纖維化的過程會扭曲肺的結構,並導致肺泡壁組織增厚,造成不可逆的肺組織氧氣交換的能力喪失、低氧血症 (hypoxemia),呼吸困難,運動不耐,甚至會造成死亡。肺纖維化疾病,尤其是特發性肺纖維化,是在臨床疾病中預後最差的疾病之一,然而目前對於肺纖維化的治療是非常有限的。在肺部結痂以後,恢復原狀很困難,唯一的治療方法是肺臟移植手術,然而只有極少數的患者能獲得移植治療。因此,目前亟需探尋新的肺纖維化分子機轉,以發展新型的肺纖維化治療方法或藥物。透過生物資訊學分析、細胞以及動物實驗,我們發現內質網蛋白 TXNDC5 (Thioredoxin domain containing 5,硫氧還蛋白5) 在肺纖維化中扮演重要的角色。在人類與小鼠肺纖維化組織與正常肺組織相較之下,TXNDC5在肺纖維化組織中的mRNA或蛋白質表現量都高度上升,其表現量也與促進肺纖維化形成的基因或蛋白質有高度相關性。人類以及老鼠的纖維母細胞在接受促進纖維化因子,轉化生長因子-β (transforming growth factor beta, TGF-β1) 刺激時,TXNDC5 的表現量會明顯增加。當TXNDC5的基因被降解 (knockdown) 後,TGF-β1刺激引起的纖維化相關蛋白質包括膠原蛋白以及 elastin 的蛋白質表現量被降低,同時也抑制了纖維母細胞受TGF-β1刺激活化為肌成纖維細胞及細胞增生的作用。在小鼠動物模型中,我們也發現TXNDC5-/-小鼠會減少因化療藥(bleomycin) 導致的肺纖維化,呼吸速率增加以及肺結構扭曲。從上述的結果,我們可以得知TXNDC5在肺纖維化扮演著重要的角色。未來將會針對TXNDC5發展出新型的肺纖維化治療藥物。 Pulmonary fibrosis (PF), a condition of excessive scarring in the lung tissue, can be idiopathic or secondary to various medical conditions. PF can lead to distorted pulmonary architecture, impaired lung function and alveolar gas exchange, resulting in hypoxemia, dyspnea, exercise intolerance and even death. Owing to the grave outcomes and tremendous health care burden associated with PF, it has become a major and growing public health problem. In spite of the advances in medicine, the incidence and mortality rate of PF remain high and options for PF therapeutics are very limited. There is a clear need to identify novel mediators and pathways of lung fibrosis to develop therapies to improve the outcomes of PF patients. Through a combined bioinformatic and experimental approach, we have recently identified an endoplasmic reticulum (ER)-resident protein thioredoxin domain containing 5 (TXNDC5) as a pivotal mediator of lung fibrosis. The mRNA and protein expression levels of TXNDC5 are highly up-regulated and positively correlate with that of extracellular matrix (ECM) proteins in lung tissues from patients with idiopathic pulmonary fibrosis (IPF) and in a mouse model of bleomycin-induced PF. In human and mouse lung fibroblasts, TXNDC5 is markedly up-regulated in response to profibrotic cytokine TGFβ1 stimulation. Knocking down TXNDC5 in lung fibroblasts leads to down-regulation of ECM proteins including collagen and elastin, as well as the inhibition of fibroblast activation/myofibroblast transformation in response to TGFβ treatment. Importantly, TXNDC5 knockout mice appear to show resistance against lung volume reduction and pulmonary fibrosis induced by bleomycin treatment. Taken together, our data suggest a critical role of TXNDC5 in the pathogenesis of pulmonary fibrosis. Targeting TXNDC5, therefore, could be a potential novel therapeutic approach to treat PF. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20480 |
DOI: | 10.6342/NTU201702521 |
全文授權: | 未授權 |
顯示於系所單位: | 藥理學科所 |
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