儿童时期腮腺炎病毒感染导致成年男性不育与支持细胞的蛋白质异戊二烯化修饰的改变相关
发布时间：2019-06-06 10:32
【摘要】：腮腺炎(Mumps)一般在5-9岁的儿童中发病,部分被感染的儿童会出现成年不育。但是对于其发病的机制目前还不是很清楚。腮腺炎病毒感染病人的睾丸组织会出现巨噬细胞的增殖并导致曲细精管的退化,即生精细胞的的大量缺失并导致不育。因此了解幼年时期睾丸支持细胞在调节免疫反应中的功能对于阐释由幼年时期精子发生的异常导致成年不育具有重要的临床意义。腮腺炎病毒感染最严重时会导致唯支持细胞综合征。而支持细胞在睾丸组织免疫特权的维持中发挥中心作用。这表明残存下来的支持细胞可能在腮腺炎病毒感染中具有重要作用。 蛋白质的异戊二烯化修饰包括香叶基化(GGPP修饰)和法尼基化(FPP修饰)两种。它们主要是通过修饰G蛋白C末端的CaaX基序,如GTPases家族的RAS超家族。这些G蛋白被修饰后,由于存在疏水性而能够结合到膜上并激活下游信号通路如MAPK通路最终发挥各种生理功能。此外,研究显示甲羟戊酸途径抑制剂statin,可以通过抑制G蛋白的香叶基化和法尼基化进而有效的抑制机体过度的炎症反应。研究结果表明蛋白质香叶基化和法尼基化修饰之间的比值在不同日龄的大鼠中表现不一样。这提示它们可能在精子的发生特别是睾丸组织的免疫调控中具有重要的功能。 本研究我们主要通过支持细胞特异性缺失GGPPS来确定蛋白质的异戊二烯化修饰在支持细胞调控免疫反应中是否有作用。还有就是这种作用是通过什么样的方式实现的。通过研究我们发现： 1.支持细胞敲除GGPPS改变蛋白质异戊二烯化可导致精原细胞而非支持细胞在出生后5天出现缺失。 2.支持细胞缺失GGPPS可导致新生小鼠炎症因子和趋化因子分泌显著上升并导致精原细胞凋亡和巨噬细胞的管腔侵润。 3.精原细胞凋亡和睾丸缺陷是由于支持细胞缺失GGPPS导致MAPK Erk1/2和NF-kB持续性激活引起。 4.支持细胞缺失GGPPS导致H-RAS的过量法尼基化修饰并导致睾丸过度的炎症反应。 5.脑心肌炎病毒(EMCV)是通过抑制GGPPS的表达来改变蛋白质的异戊二烯化修饰并导致的精子发生障碍。 综上所述,我们的研究表明支持细胞中GGPPS通过调控蛋白质异戊二烯化在幼年小鼠睾丸的发育过程中发挥重要的作用。支持细胞缺失GGPPS导致新生小鼠支持细胞中有活性的H-RAS法尼基化修饰明显升高并促发睾丸组织的炎症反应。过量的炎症反应导致新生小鼠精原细胞缺失并导致不育。这也提示我们,青春期前感染Mumps病毒导致成年不育的原因可能跟异戊二烯化的改变密切相关。我们的实验结果可能为阐释由于儿童时期的感染腮腺炎病毒并导致成年不育提供了一种新的机制。
[Abstract]:Mumps are commonly found in children between the ages of 5 and 9, and some of the infected children will have adult infertility. But the mechanism for its pathogenesis is not yet clear. The testicular tissue of the mumps virus-infected patients will cause the proliferation of macrophages and lead to the degeneration of the fine-fine tube, i. e., the large number of spermatogenic cells and the infertility. Therefore, it is of important clinical significance to understand the function of the testis-supporting cells in the regulation of immune response in the period of young age. The most severe of the mumps virus infection leads to the support of the cell syndrome. And the support cells play a central role in the maintenance of the immune privilege of the testis. This suggests that the remaining cells may play an important role in the mumps virus infection. The prenyl modification of the protein includes both the geranethylation (GPP modification) and the farnesylation (FPP modification). Species. They are mainly CaaX motifs at the end of the modified G protein C, such as the RAS superfamily of the GTPases family. Families. After these G proteins have been modified, they can be bound to the membrane due to the presence of hydrophobicity and activate downstream signaling pathways, such as MAPK pathways, to ultimately play a variety of physiological functions In addition, the study shows that the mevalonate pathway inhibitor statin can effectively inhibit the excessive inflammation of the body by inhibiting the geranethylation of the G protein and the farnesylation of the G protein, The results of the study show that the ratio of the protein geranethylation and the farnesyl modification is different in the rats of different age This suggests that they may play an important role in the immune regulation of sperm, especially in the testis. Can. We mainly determine whether the prenyl modification of the protein is in support of cell regulation and immune response by supporting the cell-specific deletion of GPPPS. That's what it's going to do. That's what it's going to do. That's true. It's through research. 1. Support for cell knock-out GPPPS to alter protein prenylation can lead to spermatogonia and non-supporting cells after birth 5 2. The absence of GPPPS in support of cell deletion could lead to a significant increase in inflammatory and chemokines in the neonatal mice and lead to the apoptosis and macrophagocytosis of the spermatogonia. 3. The apoptosis of the spermatogonia and the defect of the testis are due to the lack of GPPPS in the support of the cell deletion, which results in the activation of the MAPK Erk1/2 and NF- 4. sustained activation of kB.4. Support for cell deletion, GPPPS, resulting in an excessive anethylation of H-RAS and 5. The encephalomyocarditis virus (EMCV) is the change of the isoprene of the protein by inhibiting the expression of GPGPS. To sum up, we have shown that GPPPS in the support cells is controlled by the regulation of the protein prenyl in the juvenile mice. The development of the testis plays an important role in the development of the testis. An increase in inflammation and an inflammatory response to the tissue of the testis. An excess of inflammatory reaction leads to an increase in the number of inflammatory reactions. The lack of spermatogonial cells in the newborn mice and the infertility. This also suggests that the cause of adult infertility due to the Mimps virus before puberty It may be closely related to the change of isoprene. Our results may be to explain the mumps of mumps due to childhood.
【学位授予单位】：南京大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R725.1
本文编号：2494292
[Abstract]:Mumps are commonly found in children between the ages of 5 and 9, and some of the infected children will have adult infertility. But the mechanism for its pathogenesis is not yet clear. The testicular tissue of the mumps virus-infected patients will cause the proliferation of macrophages and lead to the degeneration of the fine-fine tube, i. e., the large number of spermatogenic cells and the infertility. Therefore, it is of important clinical significance to understand the function of the testis-supporting cells in the regulation of immune response in the period of young age. The most severe of the mumps virus infection leads to the support of the cell syndrome. And the support cells play a central role in the maintenance of the immune privilege of the testis. This suggests that the remaining cells may play an important role in the mumps virus infection. The prenyl modification of the protein includes both the geranethylation (GPP modification) and the farnesylation (FPP modification). Species. They are mainly CaaX motifs at the end of the modified G protein C, such as the RAS superfamily of the GTPases family. Families. After these G proteins have been modified, they can be bound to the membrane due to the presence of hydrophobicity and activate downstream signaling pathways, such as MAPK pathways, to ultimately play a variety of physiological functions In addition, the study shows that the mevalonate pathway inhibitor statin can effectively inhibit the excessive inflammation of the body by inhibiting the geranethylation of the G protein and the farnesylation of the G protein, The results of the study show that the ratio of the protein geranethylation and the farnesyl modification is different in the rats of different age This suggests that they may play an important role in the immune regulation of sperm, especially in the testis. Can. We mainly determine whether the prenyl modification of the protein is in support of cell regulation and immune response by supporting the cell-specific deletion of GPPPS. That's what it's going to do. That's what it's going to do. That's true. It's through research. 1. Support for cell knock-out GPPPS to alter protein prenylation can lead to spermatogonia and non-supporting cells after birth 5 2. The absence of GPPPS in support of cell deletion could lead to a significant increase in inflammatory and chemokines in the neonatal mice and lead to the apoptosis and macrophagocytosis of the spermatogonia. 3. The apoptosis of the spermatogonia and the defect of the testis are due to the lack of GPPPS in the support of the cell deletion, which results in the activation of the MAPK Erk1/2 and NF- 4. sustained activation of kB.4. Support for cell deletion, GPPPS, resulting in an excessive anethylation of H-RAS and 5. The encephalomyocarditis virus (EMCV) is the change of the isoprene of the protein by inhibiting the expression of GPGPS. To sum up, we have shown that GPPPS in the support cells is controlled by the regulation of the protein prenyl in the juvenile mice. The development of the testis plays an important role in the development of the testis. An increase in inflammation and an inflammatory response to the tissue of the testis. An excess of inflammatory reaction leads to an increase in the number of inflammatory reactions. The lack of spermatogonial cells in the newborn mice and the infertility. This also suggests that the cause of adult infertility due to the Mimps virus before puberty It may be closely related to the change of isoprene. Our results may be to explain the mumps of mumps due to childhood.
【学位授予单位】：南京大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R725.1
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相关期刊论文 前2条
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2 ;Maintaining cholesterol homeostasis: Sterol regulatory element-binding proteins[J];World Journal of Gastroenterology;2004年21期
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