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博碩士論文 etd-0630115-114124 詳細資訊
Title page for etd-0630115-114124
論文名稱
Title
探討APC基因單股缺失與Kras及P53基因突變促進膠質母細胞瘤的形成
APC Haploinsufficiency Cooperates With Kras and p53 Loss to Accelerate High Grade Glioblastoma Formation in Mice
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
71
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2015-07-23
繳交日期
Date of Submission
2015-07-30
關鍵字
Keywords
惡性腫瘤、膠質母細胞瘤、APC單股缺失、巨大細胞、生物標誌
biomarkers, Mouse models of glioblastoma multiforme, APC haploinsufficiency, giant cells, malignancy
統計
Statistics
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中文摘要
在腦部的腫瘤當中,由神經膠質細胞所引起的膠質母細胞瘤是最常見也是最致命的。相較於其他主要的癌症,在近幾十年的臨床試驗當中並無法改善生存率及預後復發的情形。讓我們不得不承認,我們對這種致命疾病背後相關的機制了解不足,導致在不斷嘗試仍然失敗。幸運的是,這幾年來透過分子病理學的研究中闡明了詳細的基因變異圖譜與膠質母細胞瘤的形成和發展的關係,包括Kras路徑的活化 (5%)、P53 (25%)和APC (2%),在這種惡性腫瘤的生物學和生物化學的基礎研究中奠定了基礎。這些分析中顯示出在特定缺失的基因當中造成一些影響並且定義膠質母細胞瘤的發展在病理階段。在這裡,我們利用帶有GFAP-cre的轉殖基因鼠來建立膠質母細胞瘤的發病的機制以及進展情形來探討在Kras活化以及P53缺失途徑當中如何去扮演合作和具體的角色和在APC單股缺失配上Kras突變活化及P53缺失的狀況下呈現血管增生、細胞壞死的區域和一些多核細胞的現象,導致加速形成膠質母細胞瘤的過程。因此,在我們極有價值的老鼠模型當中,想要探討其對於早期疾病的生物標誌進行鑑定,而我們也利用了基質輔助雷射脫附游離飛行時間質譜儀成像技術,來辨別和追蹤生物標誌。新建立的多型性膠質母細胞瘤的老鼠模型當中,將幫助我們在診斷和治療膠質母細胞瘤的方面有所改進。
Abstract
Glioblastoma multiforme (GBM) is the most common and deadest of brain tumor arising from glial cells. In contrast to other major cancers, decades of clinical trials have failed to provide appreciable survival benefit. Indeed, this continual cycle of clinical trial followed by failure has led to the clear conclusion that there is insufficient knowledge of the mechanisms underlying this lethal disease. Fortunately, molecular pathology studies have elucidated a detailed profile of genetic lesions associated with glioblastoma formation and progression—activation KRAS signaling (5%), P53 (25%) and APC (2%)—providing a foundation for investigation of the biological and biochemical basis for this malignancy. Significantly these analyses have revealed the sequential appearance of specific genetic lesions at defined histopathological stages of glioblastoma multiforme development. Here, we used a GFAP-Cre transgenic stain to determine that activated KRAS and p53 deficiency play specific and cooperative roles in the pathogenesis and progression of glioblastoma, and APC haploinsufficiency coupled with mutant Kras activation and p53 deletion resulted in the rapid progression of glioblastoma multiforme, exhibiting perivascular inflammation, large necrotic areas and some multinucleated giant cells. Thus, our mouse models are extremely valuable resources for the identification of early disease biomarkers in glioblastoma since they mimic so well the human disease. In addition, we employed proteomics and mass spectrometry based-imaging (MADLI-TOF) technologies to identify and trace candidate biomarkers in our mouse models, which will potentially help us to improve the diagnosis and treatments for glioblastoma.
目次 Table of Contents
論文審定書……………………………………………i
Abstract in Chinese……………………………………ii
Abstract in English……………………………...….…iii
Abbreviation……………………………………………v
Introduction………………………………………….... 1
Materials and Methods………………………………...10
Results…………………………………………………….19
Discussion…………………………………………………28
Figures and Tables………………………………………. 33
References……………………………………………….. 57
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