2010-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647229摘要:脂蛋白解脂酵素是一種醣蛋白,由許多種組織的實質細胞分泌後送到血管,再經由脂蛋白元CII 的活化,能將血液中的極低密度脂蛋白與乳糜微粒中的三酸甘油脂分解。如缺乏此種酵素,則上述的脂蛋白便無法被分解而積聚在體內,因而使血中的三酸甘油脂濃度上升,臨床上則會出現第一型高脂血症。而且由於高密度脂蛋白濃度的下降,也會增加發生動脈粥狀硬化疾病的機會。脂蛋白解脂酵素缺乏常由於基因的變化引起,在前次的研究中發現有三例女性國人因脂蛋白解脂酵素分子缺陷而引起脂蛋白解脂酵素缺乏之疾病。此變異型的脂蛋白解脂酵素之活性及表現量皆下降,直接定序之結果發現是第1009 位置的核甘酸由C>G,可知此位置之胺基酸在脂蛋白解脂酵素的功能上,占有很重要的角色。如果原生型或高活性的脂蛋白解脂酵素注射到病人體內,則應能將其三酸甘油脂降回正常值。因此我們將以人類基因LPL c.1009G or c.1010G 替代小鼠為模式,注射原生型或高活性的人類脂蛋白解脂酵素,及利用注射入帶有原生型或高活性的脂蛋白解脂酵素的DNA,最後再利用腺病毒血清一型作載體注入帶有原生型或高活性的脂蛋白解脂酵素的DNA 質體,以找尋作為治療此種疾病之方法,以提供病人治療之參考。<br> Abstract: Lipoprotein lipase (LPL) is a glycoprotein. After secretion by parenchymal cells,LPL becomes bound on the luminal surface of capillary endothelial cells. In thepresence of its cofactor, apolipoprotein CII (apo CII), LPL hydrolyzes triglycerides ofcirculating chylomicrons and very low-density lipoproteins to monoglycerides andfree fatty acids. LPL also has a major effect on the levels and lipid composition ofhigh-density lipoproteins. In the deficiency of LPL or apo CII, type Ihyperlipoproteinemia will occur. A defect of LPLmay be a factor in the developmentof atherosclerosis. Deficiency of LPL usually results from gene mutation. In ourprevious study, three hypertriglyceridemic female Chinese with molecular defects thatleads to deficiency of LPL activity have been identified. Direct sequencing of themutant LPL showed a C>G transversion at nucleotide position 1009 of exon 6. Thisresult demonstrated that this amino acid at this position was very important in LPLfunction.We hypothesize that if a hypertriglyceridemic patient with LPL c.1009G orc.1010G carrier receives wild type LPL protein or high activity of LPL variant proteinthen the blood triglyceride level may decrease to normal. To this purpose, we willinject wild type LPL and high activity of LPL variant protein into LPL c.1009G orc.1010G knockin mice to reduce hypertriglyceridemia.We also set out to investigatethe potential of gene therapy by hydrodynamic injection of wild type LPL and highactivity of LPL variant DNA to reduce hypertriglyceridemia of LPL c.1009G orc.1010G knockin mice. Finally intramuscular administration of a high activity of LPLvariant DNA adeno-associated virus serotype 1 will be performed in of LPL c.1009Gor c.1010G knockin mice. Through the findings, the basis for treating this kind ofdisease will be elucidated.Study of Lowering Blood Triglyceride by Variant Lipoprotein Lipase=變異脂蛋白解脂酵素降低血中三酸甘油脂之研究