臺灣博碩士論文加值系統

多囊腎病(polycystic kidney disease)是最普遍的遺傳疾病之一。患者的腎小管上皮細胞異常的增生而形成囊泡，最後導致腎臟失去功能。囊泡形成是導致多囊腎病的重要原因，但是它的機制至今還不清楚。在前胸腺素(prothymosin ��) 過量表現的基因轉殖小鼠中，我們發現腎臟也會有多囊腎病的病徵出現，因此推測前胸腺素可能是引發囊泡形成的重要因素。我們用犬類腎細胞(MDCK) 為實驗對象，探討前胸腺素過量表現在動物模式上，造成囊泡形成的可能分子機轉。我們發現前胸腺素會抑制犬類腎臟細胞形成小管，並且讓細胞走向形成囊泡的型態，因此細胞實驗跟動物模式是互相吻合的。除了在細胞實驗進一步證實前胸腺素會導致囊泡的形成之外，我們也比較其他多囊性腎疾病的動物模式中，包括Her2、 polycystin、 c-myc、 β-catenin、hepatocyte growth factor (HGF)、interleukin-6 (IL-6) 等基因轉殖小鼠，都會有多囊性腎疾病的病徵出現。我們也利用這些資訊，探討前胸腺素是否與這些分子有上下游的調控關係，而導致疾病產生。前胸腺素可增加epidermal growth factor receptor (EGFR)、Her2的表現，促使細胞增生，並且使細胞的極性(polarity)破壞。此外我們也發現polycystin-1在同型合子轉殖小鼠表現量較高，細胞實驗也證實前胸腺素會增加 polycystin-1啟動子的活性，並且兩者之間有這項調控的機制存在。總之，本研究對於多囊腎病之病因以及其和前胸腺素之關係，提供重要訊息。

Polycystic kidney disease (PKD) is one of the most common genetic diseases, which is caused by abnormal proliferation of renal epithelial cells and cyst formation in the kidney, leading to loss of function. Cyst formation plays an important role in the pathophysiology of PKD. However, its mechanism remains unclear. We have previous shown that transgenic overexpression of prothymosin α induces development of PKD. Therefore, prothymosin α may be an important factor of cystogenesis. We used MDCK canine kidney cells to study the molecular mechanism of cystogenesis. We demonstrated that prothymosin α inhibited branching tubulogenesis in MDCK cells, leading to cystogenesis in vitro. Furthermore, comparing with other animal models of PKD, including transgenic mice of polycystin-1, Her2, c-myc, and β-catenin, we investigated whether prothymosin α was involved in these signaling pathways. Our study showed that prothymosin α induced upregulation of epidermal growth factor receptor (EGFR) and Her2, leading to abnormal proliferation and loss of cell polarity. Furthermore, we found that polycystin-1 was overexpressed in the homozygous transgenic kidney. Furthermore, the activity of polycystin-1 promoter was increased in prothymosin α-overexpressing cells. Taken together, this study shed lights on the etiology of PKD and its correlation with prothymosin α .

中文摘要 ……………………………………………………… I
Abstract ……………………………………………………… II
目錄 ……………………………………………………… III
圖表目錄 ……………………………………………………… IV
縮寫 ……………………………………………………… V

緒論 ………………………………………………… 1
研究目的 ………………………………………………… 7
材料與方法 ………………………………………………… 8
實驗結果 ………………………………………………… 17
實驗討論 ………………………………………………… 21
參考文獻 ………………………………………………… 26
圖表 ………………………………………………… 41
附錄 ………………………………………………… 52
自述 ………………………………………………… 53

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