RIP3介导的细胞坏死通路在心血管慢性免疫疾病上的关键作用
发布时间：2018-07-28 14:30
【摘要】：冠心病的发生是一个世界性的致死率很高的疾病,也是一种慢性炎症疾病,炎症在疾病的发生中起到了很重要的推动作用。其中动脉粥样硬化是一个现代社会主要的致人类死亡的疾病。由于脂代谢障碍造成的血液中氧化型低密度脂蛋白(oxLDL)水平升高是形成动脉粥样硬化的主要原因。但是炎症反应是如何在疾病中起推动疾病进程的作用还并不十分清楚。在最新的研究中,本实验室报道了RIP3磷酸化是诱导细胞程序性坏死途径的关键调控蛋白。ApoE基因敲除(ApoE-/-)的小鼠是一种经典的动脉粥样硬化疾病模型,会在主动脉瓣膜和主动脉内壁形成斑块,堵塞血管。我们使用我们研发的RIP3磷酸化抗体来检测ApoE-/-小鼠动脉粥样硬化斑块,发现在动脉粥样硬化斑块的坏死腔中有磷酸化的RIP3的表达。并且,我们从动脉粥样硬化斑块中提取mRNA,检测其中的mRNA表达水平,筛选出10个炎症因子,包括IL-1α,在RIP3-/-ApoE-/-小鼠斑块中表达水平明显低于RIP3+/+ApoE-/-小鼠。RIP3+/+ApoE-/-小鼠体内的脂肪组织的淋巴细胞渗透和皮肤组织的损伤显著高于RIP3-/-ApoE-/-小鼠。Ly6chi单核细胞的百分数在RIP3+/+ApoE-/-动脉粥样硬化小鼠血液中随着病情加剧会逐渐升高。Ly6chi单核细胞的百分数在RIP3+/+ApoE-/-小鼠血液中显著高于RIP3-/-ApoE-/-小鼠。血液中的不断从骨髓中产生的免疫细胞会招募到动脉粥样硬化的斑块,来吞噬oxLDL形成泡沫细胞,巨噬细胞死亡会形成斑块,并发出死亡损伤相关的分子信号来吸引和招募更多的免疫细胞来到斑块,这个恶性循环不断的重复从而加剧着疾病的进程。但是我们发现在动脉粥样硬化疾病的发生中很重要的一点是RIP3-/-ApoE-/-小鼠的寿命远远长于RIP3+/+ApoE-/-小鼠。并且我们发现了RIP3磷酸化介导的细胞坏死是发生炎症和病理损伤的起因,起到了关键的引起小鼠死亡的作用,是扩大炎症损伤的关键点。因此,从抑制RIP3磷酸化介导的细胞坏死到在动脉粥样硬化疾病中延长REP3-/-ApoE-/-小鼠的寿命,可见RIP3在调控细胞坏死中的重要作用。所以,我们发现了受RIP3磷酸化而引起的细胞坏死是发生炎症和病理损伤的起因,是招募炎症因子扩大炎症损伤的关键点,起到了关键的引起小鼠死亡的作用。这个研究提示了RIP3磷酸化介导的程序性细胞坏死可以引起炎症反应的不断扩大和循环,这是造成动脉粥样硬化过早死亡的一个主要原因。RIP3磷酸化而引起的细胞坏死的作用不仅表现在对巨噬细胞的死亡和炎症因子表达水平上的改变,也表现在动脉粥样硬化小鼠的多种器官的损伤作用上,正是这种全面的损害加快了动脉粥样硬化小鼠的死亡。因此,细胞坏死的关键开关RIP3在生物个体上的介导坏死的作用也得到了证实,并找到了新的RIP3起作用的动物疾病模型,打开了研究RIP3作用的更广泛的领域。我们还将继续对RIP3磷酸化而引起的细胞坏死的功能和通路研究下去,希望能对促进好的药物的开发,治疗人类的疑难疾病提供一些有益的帮助。
[Abstract]:The occurrence of coronary heart disease is a worldwide disease with high mortality and a chronic inflammatory disease. Inflammation plays an important role in the occurrence of disease. Among them, atherosclerosis is a major human death disease in modern society. The oxidized low density lipoprotein in blood caused by lipid metabolism disorders. Elevated levels of oxLDL are the main cause of atherosclerosis. But the role of the inflammatory response in the disease is not very clear. In the latest study, the laboratory reported that RIP3 phosphorylation is the key regulatory protein.ApoE gene knockout (ApoE-/-) that induces cellular programmed necrosis. Mice are a classic atherosclerotic disease model, forming plaque and blocking vessels on the aortic valve and the inner wall of the aorta. We use the RIP3 phosphorylation antibody we developed to detect atherosclerotic plaques in ApoE-/- mice, and the expression of phosphorylated RIP3 in the necrotic cavity of atherosclerotic plaques. We extract mRNA from atherosclerotic plaques to detect the level of mRNA expression and screen out 10 inflammatory factors, including IL-1 alpha. The expression level in the plaque of RIP3-/-ApoE-/- mice is significantly lower than that of RIP3+/+ApoE-/- mice. The lymphatic cell infiltration and skin tissue damage in the adipose tissue of the RIP3+/+ApoE-/- mice are significantly higher than those of the RIP3-. The percentage of.Ly6chi monocytes in /-ApoE-/- mice was gradually increased in the blood of RIP3+/+ApoE-/- atherosclerotic mice. The percentage of.Ly6chi mononuclear cells was significantly higher in the blood of RIP3+/+ApoE-/- mice than in RIP3-/-ApoE-/- mice. The atherosclerotic plaques that engulf oxLDL form foam cells, the death of macrophages form plaques and emit molecular signals associated with death and injury to attract and recruit more immune cells to the plaque, which is repeated and thus exacerbates the process of disease. But we found the occurrence of atherosclerotic disease. It is important that RIP3-/-ApoE-/- mice live far longer than RIP3+/+ApoE-/- mice. And we have found that RIP3 phosphorylation mediated cell necrosis is the cause of inflammation and pathological damage, which plays a key role in causing death in mice and is the key to enlarging inflammatory damage. Therefore, it is mediated by inhibiting the phosphorylation of RIP3. Cell necrosis to prolong the life of REP3-/-ApoE-/- mice in atherosclerotic diseases can be seen as an important role of RIP3 in regulating cell necrosis. Therefore, we found that the cell necrosis caused by RIP3 phosphorylation is the cause of inflammation and pathological damage, which is the key point to recruit inflammatory factors to enlarge the inflammatory damage. This study suggests that RIP3 phosphorylation mediated programmed cell necrosis can cause the continuous expansion and circulation of inflammatory reactions, which is a major cause of premature death of atherosclerosis, the role of cell necrosis caused by.RIP3 phosphorylation not only in the death of macrophages and in the death of macrophages. The changes in the expression level of inflammatory factors are also manifested in the damage of various organs in the atherosclerotic mice, and it is this comprehensive damage that accelerates the death of atherosclerotic mice. Therefore, the role of the key switch, RIP3, to mediate necrosis in the biological individual is also confirmed, and a new RIP3 is found. The functional animal disease model has opened up a wider field of research on the role of RIP3, and we will continue to study the functions and pathways of cell necrosis caused by the phosphorylation of RIP3, and hope to provide some helpful help to the development of good drugs and the treatment of difficult diseases of human beings.
【学位授予单位】：中国农业大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R54
本文编号：2150528
[Abstract]:The occurrence of coronary heart disease is a worldwide disease with high mortality and a chronic inflammatory disease. Inflammation plays an important role in the occurrence of disease. Among them, atherosclerosis is a major human death disease in modern society. The oxidized low density lipoprotein in blood caused by lipid metabolism disorders. Elevated levels of oxLDL are the main cause of atherosclerosis. But the role of the inflammatory response in the disease is not very clear. In the latest study, the laboratory reported that RIP3 phosphorylation is the key regulatory protein.ApoE gene knockout (ApoE-/-) that induces cellular programmed necrosis. Mice are a classic atherosclerotic disease model, forming plaque and blocking vessels on the aortic valve and the inner wall of the aorta. We use the RIP3 phosphorylation antibody we developed to detect atherosclerotic plaques in ApoE-/- mice, and the expression of phosphorylated RIP3 in the necrotic cavity of atherosclerotic plaques. We extract mRNA from atherosclerotic plaques to detect the level of mRNA expression and screen out 10 inflammatory factors, including IL-1 alpha. The expression level in the plaque of RIP3-/-ApoE-/- mice is significantly lower than that of RIP3+/+ApoE-/- mice. The lymphatic cell infiltration and skin tissue damage in the adipose tissue of the RIP3+/+ApoE-/- mice are significantly higher than those of the RIP3-. The percentage of.Ly6chi monocytes in /-ApoE-/- mice was gradually increased in the blood of RIP3+/+ApoE-/- atherosclerotic mice. The percentage of.Ly6chi mononuclear cells was significantly higher in the blood of RIP3+/+ApoE-/- mice than in RIP3-/-ApoE-/- mice. The atherosclerotic plaques that engulf oxLDL form foam cells, the death of macrophages form plaques and emit molecular signals associated with death and injury to attract and recruit more immune cells to the plaque, which is repeated and thus exacerbates the process of disease. But we found the occurrence of atherosclerotic disease. It is important that RIP3-/-ApoE-/- mice live far longer than RIP3+/+ApoE-/- mice. And we have found that RIP3 phosphorylation mediated cell necrosis is the cause of inflammation and pathological damage, which plays a key role in causing death in mice and is the key to enlarging inflammatory damage. Therefore, it is mediated by inhibiting the phosphorylation of RIP3. Cell necrosis to prolong the life of REP3-/-ApoE-/- mice in atherosclerotic diseases can be seen as an important role of RIP3 in regulating cell necrosis. Therefore, we found that the cell necrosis caused by RIP3 phosphorylation is the cause of inflammation and pathological damage, which is the key point to recruit inflammatory factors to enlarge the inflammatory damage. This study suggests that RIP3 phosphorylation mediated programmed cell necrosis can cause the continuous expansion and circulation of inflammatory reactions, which is a major cause of premature death of atherosclerosis, the role of cell necrosis caused by.RIP3 phosphorylation not only in the death of macrophages and in the death of macrophages. The changes in the expression level of inflammatory factors are also manifested in the damage of various organs in the atherosclerotic mice, and it is this comprehensive damage that accelerates the death of atherosclerotic mice. Therefore, the role of the key switch, RIP3, to mediate necrosis in the biological individual is also confirmed, and a new RIP3 is found. The functional animal disease model has opened up a wider field of research on the role of RIP3, and we will continue to study the functions and pathways of cell necrosis caused by the phosphorylation of RIP3, and hope to provide some helpful help to the development of good drugs and the treatment of difficult diseases of human beings.
【学位授予单位】：中国农业大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R54
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