【摘要】：鎘是一種有毒重金屬,可經(jīng)攝取鎘污染的食物或吸入含鎘的空氣進(jìn)入人體內(nèi)。由于其在人體內(nèi)很難被清除,因而會經(jīng)血循環(huán)在多個器官與組織內(nèi)蓄積,從而導(dǎo)致全身多器官損害,如肝、腎、腦、生殖系統(tǒng)和心血管系統(tǒng)毒性。其中,心臟是鎘作用的重要靶位之一,且心臟對鎘十分敏感,低劑量鎘便能引起心臟毒性。在大鼠中低濃度鎘就即可引發(fā)心肌細(xì)胞變性、壞死以及閏盤的損傷。此外,鎘還抑制了大鼠心肌細(xì)胞傳導(dǎo)系統(tǒng)的興奮性,并可降低心肌細(xì)胞的能量代謝。然而,鎘的心臟毒性機制研究大多建立在動物模型上,而動物心臟組織與人體存在很大的區(qū)別,如心肌結(jié)構(gòu)蛋白的組成、細(xì)胞內(nèi)鈣信號的調(diào)節(jié)、電生理變化等方面。因而,建立在動物模型上的鎘心臟毒性機制并不能如實地反映人體心臟鎘中毒的情形,而正常人體心肌組織又難以獲取且不可再生,同樣不適于鎘毒性機制的研究。為了解決這一難題,本實驗通過人胚胎干細(xì)胞誘導(dǎo)分化成心肌細(xì)胞作為細(xì)胞來源,并將所得的細(xì)胞在氯化鎘處理下體外模擬正常人體暴露于鎘離子后的心臟毒性表現(xiàn),并研究其潛在的毒性機制與治療策略。在本實驗中,我們利用人胚胎干細(xì)胞系H9(Human embryonic stem cell line H9,H9 hESC)定向分化為H9來源的心肌細(xì)胞(H9-CMs),該心肌細(xì)胞同樣具有人源性。在H9-CMs經(jīng)鎘處理后,我們發(fā)現(xiàn)其形態(tài)學(xué)和電生理活動較對照組均有明顯改變,并出現(xiàn)心肌細(xì)胞凋亡現(xiàn)象。而RNA水平檢測結(jié)果提示MAPK信號通路在這一過程中有較明顯的變化,隨后我們對該信號通路加以驗證,并發(fā)現(xiàn)鎘對人源性心臟毒性可能的緩解機制。
[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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R114
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本文編號：2240704