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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 高照村(Jau-Tsuen Kao) | |
| dc.contributor.author | Yi-Shan Wong | en |
| dc.contributor.author | 翁翊珊 | zh_TW |
| dc.date.accessioned | 2021-06-15T05:00:48Z | - |
| dc.date.available | 2012-09-13 | |
| dc.date.copyright | 2010-09-13 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-07-28 | |
| dc.identifier.citation | 1. Hokanson JE, Austin MA: Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. Journal of Cardiovascular Risk 1996, 3(2):213-219.
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Brunzell,§ Ira J. Goldberg,† and Jan L. Breslow ：Catalytically inactive lipoprotein lipase expression in muscle of transgenic mice increases very low density lipoprotein uptake: Direct evidence that lipoprotein lipase bridging occurs in vivo. Proc Natl Acad Sci U S A. 1998 November 10; 95(23): 13841–13846. 99. Yasuyuki Ikedaa, Atsuko Takagib, Yuusei Nakatac, Yasuhiko Serac, Sumio Hyoudouc, Kazuko Hamamotoc, Yoshikazu Nishic, and Akira Yamamotod Novel compound heterozygous mutations for lipoprotein lipase deficiency: a G-to-T transversion at the first position of exon 5 causing G154V missense mutation and a 5' splice site mutation of intron 8 . Journal of Lipid Research, Vol. 42, 1072-1081, July 2001. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/46267 | - |
| dc.description.abstract | 脂蛋白解脂酶(LPL) 在脂質代謝方面佔有重要的角色，其主要的功能在於水解乳麋微粒和極低密度脂蛋白中的三酸甘油脂。LPL位於人類第八條染色體上，全長約30kb，包含十個exon和九個intron，LPL可以在許多組織中被合成，如脂肪組織，骨骼肌，腦及腎臟。製造出的LPL會被分泌到附近微血管，與血管壁細胞表面的HSPG結合藉以附著在微血管壁上，經由脂蛋白元CII的活化，水解乳糜微粒和極低密度脂蛋白中的三酸甘油脂，分解形成游離脂肪酸和甘油，前者可燃燒做為能量使用，或以脂質形式儲存。
LPL的缺乏常因於基因的缺陷導致，包括基因重組，插入或刪除，但大部份是胺基酸被取代造成的。LPL功能異常與臨床上的許多症狀有直接或間接關係包括，高三酸甘油脂，心血管疾病，胰臟炎和動脈硬化等。 由過去實驗室的研究結果，得知高三酸甘油脂血症病人身上找到兩種脂蛋白解脂酶基因點突變，皆位於表現子六上，分別是cDNA序列中的核苷酸由C變成G和由T變成G，都牽涉到脂蛋白解脂酶第252位置胺基酸的突變，分別突變成Val和Arg。基於此發現，實驗室利用體外定點突變方式，建構出以T7為promoter的野生型與LPL第252位置胺基酸的突變型：Leu252Val和Leu252Arg，並轉染入HEK293進行表現。在活性和表現量方面皆有明顯下降，僅有不到10%野生型的表現量。由此可推測Leu252在脂蛋白解脂酶功能上佔有重要的角色，並推測該變異應該和脂蛋白解脂酶的結構維持有著一定程度的關連性。 於是利用胺基酸定點突變在第252位置建構出其他17種胺基酸置換的衍生種轉染入HEK293細胞中進行表現。另外，為了能模擬人體內的LPL表現，以含human promoter的LPL野生型質體建構出另外19種胺基酸，於HEK293細胞進行表現，希望找到一種高度表現的脂蛋白解脂酶。依序將含有T7 promoter和human promoter的野生型和突變型質體做了細胞表現，偵測出19種L252突變型的LPL活性均遠低於野生型的活性。於T7 promoter作表現的脂蛋白解脂酶變異型的蛋白活性，於細胞培養液中偵測，均只有野生型的10%，細胞溶解物中也測出相似的趨勢。另外，以human promoter作表現的LPL變異型蛋白活性，在細胞培養液中，也只偵測到野生型蛋白活性的一半。 雖然在本實驗中並沒有發現一種LPL高活性的突變型，卻也因此再次證明L252在LPL蛋白活性中扮演重要的角色。 | zh_TW |
| dc.description.abstract | Lipoprotein lipase(LPL) gene is located on human chromosome 8. The human LPL comprises 10 exons and 9 introns spanning about 30 kb. LPL is synthesized from many tissues such as adipose tissue, skeletal muscle, brain, and so on. With activation by apoCII , LPL catalyzes hydrolysis of triglycerol(TG) from chylomicron and VLDL to free fatty acid and glycerol. High TG, obesity, coronary heart disease, pancreatitis and atherosclerosis, appear to be related to LPL. The deficient LPL gene including rearrangement, insertion, deletion or amino acid substation always influences the amount or activity of LPL. Amino acid substitute is the main reason.
In our previous study, two types of LPL gene mutation in exon 6 from high TG patients were found the cDNA nucleotide change from C to G and from T to G. These mutations change Leu to Val and Leu to Arg, respectively. The LPL activity from both mutants decreased dramatically. We supposed that Leu252 plays an important role on LPL function. In order to find a high expression of LPL, plasmids containing T7 promoter of LPL cDNA with 20 different amino acids at residue 252 were constructed, and expressed in HEK293 cell. The LPL activity was less than 10% of that of wild type for both of L252R and L252V. In order to simulate human LPL gene structure, we constructed the others 19 mutagenesis which included human promoter, and expressed in HEK293. The LPL activity of these 19 mutagenesis were lower than that of wild type. This may suggest that the importance of 252L, and any mutation will decrease its hydrolysis activity. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T05:00:48Z (GMT). No. of bitstreams: 1 ntu-99-R97424021-1.pdf: 1693824 bytes, checksum: 40523a998f07eb71eda1d8531e8c68a1 (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 總目次
總目次…………………………………………………………………………I 圖目次…………………………………………………………………………III 表目次…………………………………………………………………………III 附錄目次………………………………………………………………………III 簡稱或縮寫表…………………………………………………………………IV 中文摘要………………………………………………………………………VI 英文摘要………………………………………………………………………VIII 第一章 導論 第一節 前言…………………………………………………………1 第二節 高三酸甘油脂血症…………………………………………1 第三節 脂蛋白解脂酶的發現………………………………………2 第四節 脂蛋白解脂酶的基因構造…………………………………2 第五節 脂蛋白解脂酶的基本特性…………………………………3 第六節 脂蛋白解脂酶的分泌機轉…………………………………4 第七節 細胞內的訊息傳遞…………………………………………5 第八節 脂蛋白解脂酶的基因缺陷…………………………………5 第九節 脂蛋白解脂酶缺乏的臨床症狀……………………………6 第十節 高脂血症的治療……………………………………………6 第十一節 研究動機……………………………………………………7 第二章 實驗材料與方法 第一節 儀器設備……………………………………………………8 第二節 試藥、試劑組與材料………………………………………9 第三節 實驗方法……………………………………………………12 第三章 實驗結果 第一節 質體突變型確認……………………………………………17 第二節 人類脂蛋白解脂酶的表現…………………………………17 第三節 L252野生型與變異型對脂蛋白解脂酶活性影響…………18 第四章 討論……………………………………………………………… 19 附表……………………………………………………………………………30 附錄……………………………………………………………………………36 參考文獻………………………………………………………………………50 圖目次 圖1：以EcoRV確認二十種L252基因……………………………………………………22 圖2: 以EcoRI確認二十種PL252基因型…………………………………………………23 圖3：L252直接定序，為人類脂蛋白解脂酶第252個胺基酸定點突變結果……………24 圖4：PLPL直接定序，為人類脂蛋白解脂酶第252個胺基酸定點突變結果……………25 圖5：L252 large preparation………………………………..………………………………26 圖6: PLPL large preparation…………………………………...……………………………27 圖7：L252野生型與十九種胺基酸突變型脂蛋白解脂酶活性分析………………………28 圖8：PLPL野生型與十九種胺基酸突變型脂蛋白解脂酶活性分析……………………29 表目次 表一：世界衛生組織對高脂血症分類………………………………………30 表二：人類脂蛋白解脂酶的組成……………………………………………31 表三：人類脂蛋白解脂酶之功能與結構……………………………………33 表四：實驗過程中所需之寡核酸引子列……………………………………35 附錄目次 附錄一：定位點突變……………………………………………….……………36 附錄二：L252示意圖……………………………………………………………37 附錄三：PL252示意圖…………………………………………….….…………38 附錄一：實驗流程…………………………………………………….…………39 | |
| dc.language.iso | zh-TW | |
| dc.title | 變異脂蛋白解脂酶之研究 | zh_TW |
| dc.title | Functional studies of mutant lipoprotein lipase | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 林淑華(Shu-Wha Lin),謝絹珠(June-Hsieh Wu),江福田(Fu-Tien Chiang) | |
| dc.subject.keyword | 脂蛋白解脂酶, | zh_TW |
| dc.subject.keyword | lipoprotein lipase, | en |
| dc.relation.page | 58 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2010-07-28 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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