已知乙型轉型生長因子(transforming growth factor-β，TGF-β)之生物訊息傳遞路徑，係透過Smad蛋白質依賴性(dependent)或非Smad蛋白質依賴性訊息路徑執行其功能，進而引發細胞凋亡(apoptosis)、分化(differentiation)和細胞週期中止(cell cycle arrest)等過程，藉以調控細胞的胞內恆定(homeostasis)及發育(development)，而改變此訊息傳遞路徑則會產生嚴重的畸形(malformation)及癌症(cancer)等疾病。目前對於TGF-β/Smad訊息路徑的研究已有相當程度地了解；反之，TGF-β/非Smad蛋白質訊息傳遞路徑則尚待釐清，其中，Krüppel-like Factor 10 (KLF10)已被發現為TGF-β所誘導產生的非Smad蛋白質之一，且因其蛋白質羧基端具有三個與Sp1 (specificity protein 1)轉錄因子高相似度的鋅指(zinc finger)結構，而被歸屬於Sp/KLF家族成員之一，KLF10蛋白質可透過該鋅指結構與DNA上富含GC核苷酸的序列結合；此外，其蛋白質胺基端區域則擁有調節下游基因轉錄的作用。近年來，KLF10蛋白質陸續被發現與細胞凋亡(apoptosis)及癌化過程具相關性，但KLF10蛋白質的詳細生理功能為何仍有待釐清。為此，本論文先行以反轉錄聚合酶鏈鎖反應與西方墨點法建立Klf10的轉錄及轉譯產物在成體正常組織的表現模式，發現KLF10蛋白質大量表現在肝臟、胰臟、睪丸及副睪組織中；此外，亦以基因工程的方式進行永久性及條件性Klf10基因剔除小鼠的製造，現已分別獲得到永久及條件性Klf10基因剔除的小鼠胚胎幹細胞株與嵌合鼠，且歷經長期的配種，永久性及條件性Klf10基因剔除的嵌合鼠已確定可經由性腺傳衍(germline transmition)將剔除載體傳遞給子代，並且累積至今已獲得條件性Klf10基因剔除之同合子(Klf10floxed/floxed)小鼠及永久性Klf10基因剔除之異合子(Klf10+/-)小鼠，爾後將以此等基因剔除小鼠作為研究KLF10蛋白質在各器官中所扮演的生理角色之動物模式，用以釐清Klf10所牽連之細胞訊息傳遞路徑及其蛋白質缺失與疾病發生的關聯。

The family of transforming growth factor-β (TGF-β) cytokines, along with their corresponding signaling molecules, are master regulators of normal homeostasis and development. Consequently, alterations in these pathways lead to severe malformations and diseases, including cancer. Recent studies reveal the existence of two types of membrane-to-nucleus TGF-β signaling mechanisms, namely the Smad-dependent and non-Smad protein mediated cascades. However, the role of non-Smad proteins in the regulation of TGF-β signaling is an emerging line of active investigation, while the canonical Smad-mediated TGF-β pathway has been well studied. Krüppel-like Factor 10 (KLF10) was characterized as a non-Smad protein that was induced by TGFβ immediately. According to the protein structure, the carboxyl-terminus of KLF10 contain three Cys2His2 zinc finger domains, which is highly similarily to specificity protein 1 (Sp1), and grouped into Sp/KLF family as a new member. It has been known that KLF10 could bind to GC-rich sequences on DNA through the zinc finger domains, and the amino-terminus of KLF10 is responsible for transcriptional regulation of the target genes after binding. Recently, there are more evidence showing that KLF10 is related to apoptosis and carcinogenesis and acts as a tumor supressor. However, the detailed physiological functions of KLF10 were not known. To unveil the physiological functions of KLF10 in mammalian, we first used reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot to establish the trasncriptinal and translational expression profiles of Klf10 on adult tissues. The results of the study suggest that KLF10 is a ubiquitous protein but highly expressed in liver, pancreas, testis and epidydimis tissues. In the secondary experiment, we adopted genetic engineering method to create conventional and conditional Klf10 knockout mice. Presently, the conventional and conditional Klf10 knockout embryonic stem cell lines and chimera mice were generated. Following stringent breeding, these chimera mice had passed the knockout construct to their progeny through germline transmission. The results showed that there were twenty-seven conditional Klf10 knockout homozygous (Klf10floxed/floxed) and one conventional Klf10 knockout heterozygous (Klf10+/-) mice, as evidences that have shown by genomic-PCR with stingent primer design.
Thereafter, these genetic engineered mice could be used as a model to examine the physiological roles of KLF10 in various organs in vivo. By using this model, it will uncover the signaling mechanism of KLF10 and the relationship between KLF10 protein loss and diseases.

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