标题: | 针对动脉粥状硬化性疾病之功能性分子感测成像及活体药物筛选 Functional sensing, molecular imaging and drug screening in vivo targeting atherosclerosis |
作者: | 杨逸群 Yang, Yi-Cyun 廖奕翰 Liau, Ian 应用化学系硕博士班 |
关键字: | 动脉粥状硬化;中风;心肌梗塞;拉曼光谱;共轭焦显微镜;史达汀;药物筛选;斑马鱼;不稳定性斑块;活性氧化物;量子点;发炎反应;Atherosclerosis;Stroke;Myocardial infarction;Raman spectroscopy;Confocal microscopy;Statin;Drug screening;Zebrafish;Vulnerable plaque;Reactive oxygen species;Quantum dot;Inflammation |
公开日期: | 2013 |
摘要: | 动脉粥状硬化性心血管疾病 (atherosclerotic cardiovascular disease) 为已开发国家人民死亡的主因之一。其致命的原因在于血管壁内的不稳定性斑块 (vulnerable plaque) 破裂后所引起的急性血栓 (acute thrombosis) 所造成的缺血性中风 (ischemic stroke) 及心肌梗塞 (myocardial infarction)。动脉粥状硬化之致病过程开始于低密度脂蛋白 (low-density lipoprotein, LDL) 堆积于血管内壁,以及其受活性氧化物质 (reactive oxygen species) 氧化修饰为氧化之低密度脂蛋白 (oxidatively modified LDL).氧化之低密度脂蛋白为动脉粥状硬化斑块发炎的主要刺激源,而斑块的发炎程度则影响到斑块的稳定程度或易破裂的程度。因此,精确评估血管壁上之低密度脂蛋白堆积、氧化修饰以及斑块发炎程度,不但有助于心血管疾病之临床诊断,也对相关药物的开发有相当助益。基于上述工作于医药发展上之重要性,学生在博士期间的工作主要在开发针对动脉粥状硬化之分子探针及光谱及影像检测方法.完成的具体工作包含 (1) 开发一个可针对活性氧化物进行”绝对定量”之萤光分子探针;(2) 建立一个评估动脉粥状硬化斑块发炎程度的萤光分子影像检测法;(3) 建立一个于活体斑马鱼以萤光成像与拉曼光谱技术进行动脉粥状硬化药物筛选的平台。我的工作突破了以往的研究限制并首次展现 (1) 对细胞内外之活性氧化物分泌进行浓度绝对定量;(2) 于活体动物(斑马鱼)内探讨动脉粥状硬化斑块的发炎程度;(3) 于活体斑马鱼血管原位评估低密度脂蛋白堆积及氧化修饰,并将此方法应用于药物筛选。学生期待以上方法及技术能对往后动脉粥状硬化的基础研究有所助益,并协助相关药物之开发以及临床诊断。 Atherosclerotic cardiovascular disease is a leading cause of death. Sudden rupture of a vulnerable atherosclerotic plaque triggers thrombosis and causes a deadly event such as ischemic stroke or myocardial infarction. Pathogenesis of atherosclerosis includes an accumulation of low-density lipoprotein (LDL) in the vascular wall and its oxidative modification by endogenous reactive oxygen species (ROS). Vascular inflammation induced by the accumulation of oxidatively modified LDL (oxLDL) plays a key role in the vulnerability of atherosclerotic plaque and increases the risk of cardiovascular thrombotic events. As a result, the development of methods for the assessment of such symptoms (i.e., vascular accumulation of LDL and its oxidative modification, and plaque inflammation) is important for the clinical diagnosis, and for the evaluation of the therapeutic efficacy of medications, targeting atherosclerosis. Toward this end, my PhD work focuses on the development of: (1) A quantum dots based molecular probe for the real-time and absolute quantifying ROS in vivo; (2) Fluorescence molecular imaging for the evaluation of plaque inflammation; (3) A platform (comprising confocal fluorescence imaging, Raman spectral analysis, and hypercholesterolemic zebrafish) for the direct assessment of vascular LDL deposition and oxidation in vivo and in situ, and its application for drug screening. Facilitated with these unique approaches, I demonstrated for the first time (1) Absolute quantification of endogenous HOCl in leukocyte; (2) Evaluation of the inflammation of individual atherosclerotic plaques in zebrafish in vivo; (3) Evaluation of the therapeutic activity of anti-atherosclerotic drugs (Atorvastatin and Ezetimibe) on individual plaques in zebrafish in vivo. I envisage that my approach will not only improve our understanding of atherogenesis but also expedite the screening of drugs and clinical diagnosis targeting atherosclerosis. |
URI: | http://140.113.39.130/cdrfb3/record/nctu/#GT079825815 http://hdl.handle.net/11536/75267 |
显示于类别: | Thesis |