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標題: | 探討含硫氧還原蛋白結構域的5號蛋白質(TXNDC5) 於順鉑藥物誘發之睪丸損傷化中所扮演的角色 Investigate the role of thioredoxin domain-containing protein 5 (TXNDC5) in cisplatin-induced testicular damage |
作者: | 陳葉子 Chanakan Arprayoon |
指導教授: | 蔡沛學 PEI-SHIUE TSAI |
關鍵字: | cisplatin,TXNDC5,睪丸損傷化,活性含氧物,內質網蛋白質, cisplatin,TXNDC5,testicular damage,ROS,ER protein, |
出版年 : | 2022 |
學位: | 碩士 |
摘要: | Cisplatin 為常見用於治療不同類型腫瘤之化療藥物。雖其治療效果佳,但治療過程中產生的過量活性含氧物質對於生殖系統,尤其是睪丸會產生嚴重且不可逆之副作用。Cisplatin 造成的副作用包含睪丸組織的損傷,生殖細胞的凋亡,以及生精小管間隙過度細胞外基質的累積。先前研究指出 thioredoxin domain containing 5 (TXNDC5) 為內質網中的雙硫異構酶,與許多器官的纖維化相關,其中包含 cisplatin 所導致的睪丸纖維化 。本篇研究顯示,cisplatin的介入對於生精細胞造成嚴重損傷,睪丸中的TXNDC5 與其他與纖維化相關的蛋白質和基因表現如TGFβ-1、COL1A1 及αSMA都有顯著性的上升。小鼠在剔除TXNDC5 後,發現減緩cisplatin所造成的睪丸損傷,也保留較多生精細胞層。在TXNDC5基因剔除小鼠中,睪丸內的活性含氧物質含量顯著降低,也間接導致細胞凋亡的比例減少。我們結果指出TXNDC5 基因剔除有助於減輕cisplatin所導致的睪丸損傷,並減少與纖維化相關基因與蛋白質表現。調控TXNDC5的表現與功能可能對於改善化學療法導致的睪丸損傷與纖維化有潛在的影響力,並有助接受化療的病人降低不孕症狀和改善其生殖能力。 Cisplatin is the common chemotherapy drug used to treat various kinds of tumors. Even though cisplatin is effective, the side effect on reproductive organs due to excessive production of reactive oxygen species, especially in testis, is severe and irreversible. Side effects of cisplatin in testis were shown in severe testicular damage, including germ cell apoptosis, and excessive accumulation of extracellular matrix (ECM) in the interstitial area of the testis which resulted in fibrosis. Recently, one ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), was discovered to be involved in the progression of fibrosis in many organs, including in the testis induced by cisplatin. This study demonstrated that after cisplatin administration, spermatogenic cells were significantly destroyed, TXNDC5 and other fibrosis-related protein and gene expression, including TGFβ-1, COL1A1, and αSMA were upregulated. Deletion of TXNDC5 showed the mitigating effect of cisplatin-induced testicular damage by preserving more spermatogenic cells layer. The knockdown mice showed decreased fibrotic protein and gene expression and reduced ECM accumulation in testicular tissue. Furthermore, testicular ROS production from the cisplatin administration was decreased in TXNDC5 knockdown mice with a reduced percentage of cell apoptosis. Our results demonstrate that TXNDC5 is likely to play an important role in cisplatin-induced testicular damages as gene knockdown of TXNDC5 showed reduced testicular damages and down-regulation on the expression of fibrosis-related genes. Targeting TXNDC5 could be a novel therapeutic approach to alleviate the severity of chemotherapy-induced testicular damage and thereby recover the effect of male infertility and reproduction outcomes in chemotherapy-receiving cancer patients. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/91919 |
DOI: | 10.6342/NTU202201862 |
全文授權: | 同意授權(限校園內公開) |
顯示於系所單位: | 獸醫學系 |
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