RIP3介導的細胞壞死通路在心血管慢性免疫疾病上的關(guān)鍵作用
發(fā)布時間：2018-07-28 14:30
【摘要】：冠心病的發(fā)生是一個世界性的致死率很高的疾病,也是一種慢性炎癥疾病,炎癥在疾病的發(fā)生中起到了很重要的推動作用。其中動脈粥樣硬化是一個現(xiàn)代社會主要的致人類死亡的疾病。由于脂代謝障礙造成的血液中氧化型低密度脂蛋白(oxLDL)水平升高是形成動脈粥樣硬化的主要原因。但是炎癥反應是如何在疾病中起推動疾病進程的作用還并不十分清楚。在最新的研究中,本實驗室報道了RIP3磷酸化是誘導細胞程序性壞死途徑的關(guān)鍵調(diào)控蛋白。ApoE基因敲除(ApoE-/-)的小鼠是一種經(jīng)典的動脈粥樣硬化疾病模型,會在主動脈瓣膜和主動脈內(nèi)壁形成斑塊,堵塞血管。我們使用我們研發(fā)的RIP3磷酸化抗體來檢測ApoE-/-小鼠動脈粥樣硬化斑塊,發(fā)現(xiàn)在動脈粥樣硬化斑塊的壞死腔中有磷酸化的RIP3的表達。并且,我們從動脈粥樣硬化斑塊中提取mRNA,檢測其中的mRNA表達水平,篩選出10個炎癥因子,包括IL-1α,在RIP3-/-ApoE-/-小鼠斑塊中表達水平明顯低于RIP3+/+ApoE-/-小鼠。RIP3+/+ApoE-/-小鼠體內(nèi)的脂肪組織的淋巴細胞滲透和皮膚組織的損傷顯著高于RIP3-/-ApoE-/-小鼠。Ly6chi單核細胞的百分數(shù)在RIP3+/+ApoE-/-動脈粥樣硬化小鼠血液中隨著病情加劇會逐漸升高。Ly6chi單核細胞的百分數(shù)在RIP3+/+ApoE-/-小鼠血液中顯著高于RIP3-/-ApoE-/-小鼠。血液中的不斷從骨髓中產(chǎn)生的免疫細胞會招募到動脈粥樣硬化的斑塊,來吞噬oxLDL形成泡沫細胞,巨噬細胞死亡會形成斑塊,并發(fā)出死亡損傷相關(guān)的分子信號來吸引和招募更多的免疫細胞來到斑塊,這個惡性循環(huán)不斷的重復從而加劇著疾病的進程。但是我們發(fā)現(xiàn)在動脈粥樣硬化疾病的發(fā)生中很重要的一點是RIP3-/-ApoE-/-小鼠的壽命遠遠長于RIP3+/+ApoE-/-小鼠。并且我們發(fā)現(xiàn)了RIP3磷酸化介導的細胞壞死是發(fā)生炎癥和病理損傷的起因,起到了關(guān)鍵的引起小鼠死亡的作用,是擴大炎癥損傷的關(guān)鍵點。因此,從抑制RIP3磷酸化介導的細胞壞死到在動脈粥樣硬化疾病中延長REP3-/-ApoE-/-小鼠的壽命,可見RIP3在調(diào)控細胞壞死中的重要作用。所以,我們發(fā)現(xiàn)了受RIP3磷酸化而引起的細胞壞死是發(fā)生炎癥和病理損傷的起因,是招募炎癥因子擴大炎癥損傷的關(guān)鍵點,起到了關(guān)鍵的引起小鼠死亡的作用。這個研究提示了RIP3磷酸化介導的程序性細胞壞死可以引起炎癥反應的不斷擴大和循環(huán),這是造成動脈粥樣硬化過早死亡的一個主要原因。RIP3磷酸化而引起的細胞壞死的作用不僅表現(xiàn)在對巨噬細胞的死亡和炎癥因子表達水平上的改變,也表現(xiàn)在動脈粥樣硬化小鼠的多種器官的損傷作用上,正是這種全面的損害加快了動脈粥樣硬化小鼠的死亡。因此,細胞壞死的關(guān)鍵開關(guān)RIP3在生物個體上的介導壞死的作用也得到了證實,并找到了新的RIP3起作用的動物疾病模型,打開了研究RIP3作用的更廣泛的領域。我們還將繼續(xù)對RIP3磷酸化而引起的細胞壞死的功能和通路研究下去,希望能對促進好的藥物的開發(fā),治療人類的疑難疾病提供一些有益的幫助。
[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.
【學位授予單位】：中國農(nóng)業(yè)大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R54
本文編號：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.
【學位授予單位】：中國農(nóng)業(yè)大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R54
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