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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 周子賓(Tze-Bin Chou) | |
| dc.contributor.author | Yu-Chieh Chien | en |
| dc.contributor.author | 簡玉潔 | zh_TW |
| dc.date.accessioned | 2021-06-08T06:08:48Z | - |
| dc.date.copyright | 2007-07-19 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-07-14 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/25316 | - |
| dc.description.abstract | 第一型神經纖維瘤(NF1)是常見的顯性遺傳性疾病之一。其發生率高達四千至五千分之一，並且已有研究證明此疾病與位於第十七條染色體長臂上之NF1基因異常有關。NF1的基因產物稱為neurofibromin，此蛋白質含有一段功能性片斷稱為GRD(GAP-related domain)與鳥嘌呤核苷三磷酸活化蛋白質相似，可以負向調控Ras途徑之活化。即使在具有NF1遺傳病史的同一家族中，NF1病患之臨床症狀仍然相當多樣化。許多過去的研究皆試圖研究出NF1基因型(genotype)與NF1病患表型(phenotype)之間的相關性。幾乎所有NF1病患都具有神經纖維瘤的病徵，且2% 的NF1病患之神經纖維瘤會惡化成惡性周邊神經髓鞘腫瘤 (malignant peripheral nerve sheath tumor)。過去關於惡性周邊神經髓鞘腫瘤的研究中，曾經發現因為p53基因突變，或是其他細胞週期調控因子缺陷影響p53的活性。這個結果顯示p53與NF1基因變異可能同時影響神經纖維瘤惡化成惡性周邊神經髓鞘腫瘤的過程，因此引發了我們研究p53在神經纖維瘤中扮演的角色。
在本篇研究報告中，我們分析NF1基因以及p53基因在第一型神經纖維瘤中的表現。我們利用MLPA (multiplex ligation-dependent probe amplification)分析試劑分析兩基因序列變異，以定量即時性PCR(quantitative real-time PCR)定量訊息RNA(mRNA)含量，並結合組織切片免疫染色觀察兩基因之蛋白質產物在神經纖維瘤中的表現量。檢測結果顯示，在由26位NF1病患取下之27個神經纖維瘤檢體中，我們發現14 個(51.85%)檢體中之NF1基因有單一或多重exon缺失的現象；僅有2個(7.4%)病例帶有p53基因之單一exon缺失現象。在基因訊息RNA(mRNA)表現的實驗中，我們觀察到在28個檢體中有16個(57.14%)檢體之NF1訊息RNA之表現量下降；有21個(75%)檢體之p53訊息RNA之表現量下降。另外，根據組織切片免疫染色方法，我們分別在與周邊組織不具有良好分界的神經纖維瘤中觀察到7/12 (58.33%)的組織切片中p53蛋白質之免疫染色強度較高，而在具有良好分界的神經纖維瘤中則僅有4/11 (36.36%)的組織切片中p53蛋白質之免疫染色強度較高。這個結果可能暗示p53蛋白質的表現與神經纖維瘤的表型有某種程度的關聯性。歸納我們的實驗結果，我們推測在第一型神經纖維瘤中，p53基因與NF1基因可能以非直接的的方式互相影響。 | zh_TW |
| dc.description.abstract | Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic diseases. It has a high prevalence of approximately 1 in 4000-5000 and has been proved was caused by defects on the NF1 gene. The gene product of NF1 is named neurofibromin, containing a GRD (GAP-related domain) domain which can negatively modulate Ras pathway. The clinical expression and severity of NF1 patients is diverse, even within families. The penetrance of NF1 is close to 100%, and approximately 50% of cases carry spontaneous mutations. Nearly all NF1 patients eventually develop neurofibromas, and malignant transformation of neurofibromas may form malignant peripheral nerve sheath tumor (MPNST) which occurs in about 2% of NF1 patients. Previous studies of NF1-related MPNST have found p53 inactivation by mutation or other defects of cell cycle regulators which can affect p53 activity. These results indicate that p53 may participate in the tumorigenesis from neurofibromas to MPNST and raise our interest in the role of p53 in NF1-related neurofibroma.
We investigate the NF1 and p53 gene expression from genomic level to protein level in NF1-related neurofibromas. We perform MLPA (multiplex ligation-dependent probe amplification) analysis assay on genomic DNA, quantitative real-time PCR technique on the mRNA, and combined immunohistochemistry method to evaluate the protein expression of NF1 and p53 gene in neurofibromas. The results of MLPA analysis showed 14 (51.85%) tumors with single or multiple NF1 exon deletion and 2 (7.4%) cases with single exon deletion of p53 gene in total of 27 tumor samples from 26 NF1 patients. The down-regulated expression of NF1 mRNA was found in 16 samples of 28 neurofibrmas (57.14%). Up-regulated expression of p53 mRNA was observed in 21 samples of 28 neurofibromas (75%). The higher immunoreactivity of p53 protein expression was obeserved in 7/12 (58.33%) ill-defined neurofibromas, and in 4/11 (36.36%) well-defined neurofibromas. This result implicated possible correlations of the p53 protein expression with the phenotype of neurofibromas. In summary, we proposed that p53 may interplay with NF1 but not directly in the NF1-related neurofibroma formation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T06:08:48Z (GMT). No. of bitstreams: 1 ntu-96-R94b43028-1.pdf: 2735700 bytes, checksum: 036edad9cd7ed35a8e577a4423ce225c (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | 口試委員審定書…………………………………………………………………………i
誌謝……………………………………………………………………………………...ii 中文摘要………………………………………………………………………………..iii Abstract……...………………………………………………….……………………..iiii Table of Content ..…………………………………………………..…………………..1 List of Figures…………...………………………………………….………………......3 List of Tables…………...………………………………………….………………........4 Introduction…………..……………………………………………..…………………..5 1. Neurofibromatosis type 1………………………………………………………..5 2. The NF1 gene……………………………………………..……………………..5 3. The functions of neurofibromin……………………………………………….....7 4. Regulation of neurofibromin expression………………………………………...9 5. Mutations of the NF1 gene……………………………………………………..10 6. Pathophysiology of NF1………………………………………………………..12 7. Animal models of NF1…………………………………………………………15 8. The p53 gene in NF1…………………………………………………………...17 Materials and Methods……………………………………………………………….20 1. Patients and samples……………………………………………………………20 2. DNA extraction and purification from fresh or frozen solid tissue…………….21 3. DNA extraction and purification from whole blood……………………………22 4. MLPA analysis………………………………………………………………….23 5. RNA extraction ………………………………………………………………...26 6. cDNA preparation………………………………………………………………27 7. Quantitative real-time PCR…………………………………………………….27 8. Immunohictochemistry…………………………………………………………29 9. Polymerase chain reaction……………………………………………………...30 10. TOPO TA cloning………………………………………………………………31 Result…………………………………………………………………………………..33 1. Single or multiple exons deletion of NF1 gene analyzed by MLPA method….....33 2. Confirmation of NF1 single exon deletion…………………………………..…...36 3. Quantitative analysis of NF1 exon 5, 7, 17, 19A, 45 and 47 by real-time PCR….36 4. Single exon deletion of p53 gene in neurofibroma analyzed by MLPA method…37 5. mRNA expression level of NF1 gene in neurofibroma………………………......38 6. mRNA expression level of p53 gene in neurofibroma………………………..….39 7. Neurofibromin expression in neurofibromas………………………………..…....39 8. p53 protein expression in Neurofibromas…………………………………..…....40 Discussion……………………………………………………………………………...41 1. Intragenic exon deletion of NF1 gene may contribute to the neurofibromas formation…………………………………………………………………………41 2. Aberrant expression of NF1 gene in neurofibroma ………………………...........46 3. Mutation of p53 gene seems not directly involved in neurofibromas formation...48 4. Elevated p53 protein expression may correlate with the phenotype of neurofibromas…………………………………………………………………….50 5. Conclusion………………………………………………………………………..52 Reference List………………………………………………………………………….54 Figures…………………………………………………………………………………69 Tables…………………………………………………………………………………..87 Supplements…………………………………………………………………………...96 | |
| dc.language.iso | en | |
| dc.subject | 第一型神經纖維瘤 | zh_TW |
| dc.subject | 基因 | zh_TW |
| dc.subject | NF1 | en |
| dc.subject | p53 | en |
| dc.subject | neurofibroma | en |
| dc.title | 第一型神經纖維瘤中NF1基因與p53基因表現之探討 | zh_TW |
| dc.title | The study of NF1 and p53 gene expression in NF-1 related neurofibroma | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 吳雅慧,林光輝,柯逢春 | |
| dc.subject.keyword | 第一型神經纖維瘤,基因, | zh_TW |
| dc.subject.keyword | neurofibroma,NF1,p53, | en |
| dc.relation.page | 96 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2007-07-17 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 分子與細胞生物學研究所 | zh_TW |
| 顯示於系所單位： | 分子與細胞生物學研究所 | |
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