臺灣博碩士論文加值系統

肝臟為體內最大的腺體，在體內扮演著維持恆定的重要角色。當肝臟細胞受到傷害時，肝臟會藉由快速進行細胞分裂，修補不足的體積及受傷的肝細胞，以達到回復正常功能。先前研究發現，在肝再生的過程中會表現胰臟外分泌基因，如胰臟澱粉酶(Amy2)、胰臟脂酶(Pnlip) 等。本實驗室藉由小鼠肝再生微陣列分析，發現在肝再生early G1 phase有44個胰臟相關基因同步表現(syn-expression)，並以real time RT-PCR做驗證。我們同時觀察到五群聚集於染色絲特定區段的胰臟外分泌基因群於肝再生早期同步表現。我們先以Chr6, 40.8~41.6 Mb區域作為首要研究，初步經由RT-PCR以及micrococcal nuclease digestion assay驗證胰臟外分泌基因群於肝再生過程中，受到染色絲結構的重新建構，調控其於肝再生過程中，同時大量表現。藉由文獻資料及預測工具，我們歸納出胰臟外分泌基因群可能受到Ptf1a、Ipf1、Nr3c1 (GR)轉錄因子的共同調控。採用染色絲免疫沉澱分析，證明這些胰臟外分泌基因群啟動子區域的結合位置處於活化狀態。有待進ㄧ步利用各轉錄因子之抗體進行染色絲免疫沉澱以資證明，是否直接參與調控胰臟外分泌基因群於肝再生早期的表現。
切肝後，肝臟大量表現胰臟澱粉酶以及脂酶，促使我們想去了解肝臟肝糖及脂質的表現狀況，因此我們藉由PAS以及Oil Red O染色，觀察到肝再生早期肝糖快速分解，並同時具有脂質堆積的現象，而於切肝後48小時進行脂解作用，同時觀察到肝糖生成。配合胰臟澱粉酶之免疫組織染色結果，發現肝臟表現胰臟澱粉酶與脂質堆積量呈正相關性，而與肝糖貯存量以及細胞分裂進行呈負相關性。我們推論肝再生過程中，是否受到同一調控因子的作用，而使其具有如此的相關性。先前已有文獻說明GR參與糖新生及脂解作用，亦扮演著聚集調控染色絲重新建構之複合物以及調控胰臟外分泌基因轉錄因子Ptf1a、Ipf1的角色。因此可更進ㄧ步探討Nr3c1於肝再生所扮演的角色，以及是否直接或間接地調控肝再生早期胰臟外分泌基因群同步大量表現。
已有臨床實例及研究指出，切肝後胰臟具有發炎現象。引發我們想去探討切肝後，肝臟與胰臟之間具有互相影響的可能性。藉由觀察切肝後胰臟表現發炎相關蛋白Reg2以及肝臟表現胰臟外分泌蛋白Amy2的趨勢，具有正相關性。我們推論肝再生過程中胰臟受到傷害，進而促使肝臟表現胰臟外分泌基因群以補償胰臟受損的外分泌功能，維持體內恆定。

Hepatocytes rarely divide but rapidly regenerate upon severe tissue losses by chemical or physical injuries. Numerous reports revealed live-to-pancreas metaplasia in vitro, in vivo, and in patients with tumors in cirrhotic liver. The molecular mechanism dictating the mutual interaction between adult liver and pancreas, however, is uncertain. In a global transcriptome study we detected activation of a cluster of 44 pancreatic exocrine genes during partial hepatectomy (PHx) induced mouse liver regeneration. Syn-expression of selected genes, including pancreas transcription factors, Ptf1a and Ipf, at early G1 phase was confirmed by RT-qPCR. Interestingly, we found that many of the co-expressed genes are congregated in specific chromosomal loci. We analyzed 31 genes of trypsinogen/trypsin genes in the 40.8-41.6 Mb region of chromosome 6 B1 using RT-PCR. All the trypsinogen/trypsin genes that are differentially expressed in gastrointestinal tract, were up-regulated while testis trypsinogens (BC048599, 1700074P13Rik) and all the gene segments of the TCR Vβ locus were not expressed. The results suggested that this chromosomal domain maybe under a coordinated regulation during liver regeneration. Based on the literature data and bioinformatics prediction tools, we identified the binding sites of three transcription factors, Ptf1a, Ipf1 and Nr3C1, common to all the exocrine genes. Whether they coordinately regulate this ectopic liver expression is to be determined.

Ectopic expression of pancreatic amylase and lipase in liver prompted us to examine the status of glycogen and lipid in the regenerating livers using specific stains of PAS and Oil Red O. Our preliminary results showed that expression of pancreatic amylase correlated with accumulation of lipid while the amount of glycogen accumulated is negatively correlated with progression of cell cycle progression during liver regeneration. Nr3c1 is involved in both glyconeogenesis, lypolysis and in chromatin remodeling. It will be interesting to explore the possibility of Nr3c1 being a master regulator for this ectopic expression program.

We also detected transient elevation of Reg2 protein and abnormal organelle structures in the pancreatic acinar cells of mice undergone partial hepatectomy. A positive correlation exists between liver ectopic expression of pancreatic amylase and Reg2 expression in pancreatic acinar cells suggesting an interaction at the organ level. It remains to be determined whether ectopic liver expression of pancreatic exocrine genes contributes to early signaling of liver regeneration or to compensation of the transient pancreatic damages from the altered blood flow during partial hepatectomy.

中英文名詞縮寫對照表……………………………1
中文摘要……………………………………………2
英文摘要……………………………………………3
緒論 ………………………………………………4
實驗材料 …………………………………………12
實驗方法………………………………………… 16
一、小鼠部分切肝模式 …………………………16
二、組織固定包埋 ………………………………16
三、Oil Red O stain……………………………16
四、免疫組織染色 ………………………………17
五、PAS染色 ……………………………………19
六、蛋白質電泳分析 ……………………………19
七、RNA分析 ……………………………………21
八、組織染色絲免疫沉澱分析 …………………23
九、微球菌核酸酶切割分析 ……………………26
十、微陣列分析 …………………………………27
實驗結果 …………………………………………28
討論 ………………………………………………41
參考文獻 …………………………………………45
圖表 ………………………………………………55
附錄 ………………………………………………82

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