重金属镉对人多能干细胞衍生的心肌细胞毒性的机制研究
发布时间：2018-09-13 09:09
【摘要】：镉是一种有毒重金属,可经摄取镉污染的食物或吸入含镉的空气进入人体内。由于其在人体内很难被清除,因而会经血循环在多个器官与组织内蓄积,从而导致全身多器官损害,如肝、肾、脑、生殖系统和心血管系统毒性。其中,心脏是镉作用的重要靶位之一,且心脏对镉十分敏感,低剂量镉便能引起心脏毒性。在大鼠中低浓度镉就即可引发心肌细胞变性、坏死以及闰盘的损伤。此外,镉还抑制了大鼠心肌细胞传导系统的兴奋性,并可降低心肌细胞的能量代谢。然而,镉的心脏毒性机制研究大多建立在动物模型上,而动物心脏组织与人体存在很大的区别,如心肌结构蛋白的组成、细胞内钙信号的调节、电生理变化等方面。因而,建立在动物模型上的镉心脏毒性机制并不能如实地反映人体心脏镉中毒的情形,而正常人体心肌组织又难以获取且不可再生,同样不适于镉毒性机制的研究。为了解决这一难题,本实验通过人胚胎干细胞诱导分化成心肌细胞作为细胞来源,并将所得的细胞在氯化镉处理下体外模拟正常人体暴露于镉离子后的心脏毒性表现,并研究其潜在的毒性机制与治疗策略。在本实验中,我们利用人胚胎干细胞系H9(Human embryonic stem cell line H9,H9 hESC)定向分化为H9来源的心肌细胞(H9-CMs),该心肌细胞同样具有人源性。在H9-CMs经镉处理后,我们发现其形态学和电生理活动较对照组均有明显改变,并出现心肌细胞凋亡现象。而RNA水平检测结果提示MAPK信号通路在这一过程中有较明显的变化,随后我们对该信号通路加以验证,并发现镉对人源性心脏毒性可能的缓解机制。
[Abstract]:Cadmium is a toxic heavy metal that enters the body by ingesting cadmium-contaminated food or inhaling cadmium-contaminated air. Because it is difficult to remove in the body, it accumulates in many organs and tissues through the blood circulation, resulting in systemic multiple organ damage, such as liver, kidney, brain, reproductive system and cardiovascular system toxicity. In addition, cadmium inhibits the excitability of the conduction system of rat cardiomyocytes and reduces the energy metabolism of cardiomyocytes. Much of the research on the mechanism of cardiotoxicity is based on animal models, but there are great differences between animal heart tissue and human body, such as the composition of cardiac structural proteins, intracellular calcium signal regulation, electrophysiological changes and so on. In order to solve this problem, human embryonic stem cells were induced to differentiate into cardiomyocytes as a source of cells, and the obtained cells were treated with cadmium chloride to simulate the normal human heart exposed to cadmium ions in vitro. In this experiment, we used human embryonic stem cell line H9 (H9 hESC) to differentiate into H9-derived cardiomyocytes (H9-CMs), which were also human-derived. After cadmium treatment, we found that H9-CMs were morphological and electrogenic. The results of RNA level test indicated that MAPK signaling pathway had obvious changes in this process, and then we verified this signaling pathway and found that cadmium might alleviate human cardiac toxicity.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R114
，
本文编号：2240704
[Abstract]:Cadmium is a toxic heavy metal that enters the body by ingesting cadmium-contaminated food or inhaling cadmium-contaminated air. Because it is difficult to remove in the body, it accumulates in many organs and tissues through the blood circulation, resulting in systemic multiple organ damage, such as liver, kidney, brain, reproductive system and cardiovascular system toxicity. In addition, cadmium inhibits the excitability of the conduction system of rat cardiomyocytes and reduces the energy metabolism of cardiomyocytes. Much of the research on the mechanism of cardiotoxicity is based on animal models, but there are great differences between animal heart tissue and human body, such as the composition of cardiac structural proteins, intracellular calcium signal regulation, electrophysiological changes and so on. In order to solve this problem, human embryonic stem cells were induced to differentiate into cardiomyocytes as a source of cells, and the obtained cells were treated with cadmium chloride to simulate the normal human heart exposed to cadmium ions in vitro. In this experiment, we used human embryonic stem cell line H9 (H9 hESC) to differentiate into H9-derived cardiomyocytes (H9-CMs), which were also human-derived. After cadmium treatment, we found that H9-CMs were morphological and electrogenic. The results of RNA level test indicated that MAPK signaling pathway had obvious changes in this process, and then we verified this signaling pathway and found that cadmium might alleviate human cardiac toxicity.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R114
，
本文编号：2240704
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