【摘要】：腮腺炎(Mumps)一般在5-9歲的兒童中發(fā)病,部分被感染的兒童會(huì)出現(xiàn)成年不育。但是對(duì)于其發(fā)病的機(jī)制目前還不是很清楚。腮腺炎病毒感染病人的睪丸組織會(huì)出現(xiàn)巨噬細(xì)胞的增殖并導(dǎo)致曲細(xì)精管的退化,即生精細(xì)胞的的大量缺失并導(dǎo)致不育。因此了解幼年時(shí)期睪丸支持細(xì)胞在調(diào)節(jié)免疫反應(yīng)中的功能對(duì)于闡釋由幼年時(shí)期精子發(fā)生的異常導(dǎo)致成年不育具有重要的臨床意義。腮腺炎病毒感染最嚴(yán)重時(shí)會(huì)導(dǎo)致唯支持細(xì)胞綜合征。而支持細(xì)胞在睪丸組織免疫特權(quán)的維持中發(fā)揮中心作用。這表明殘存下來(lái)的支持細(xì)胞可能在腮腺炎病毒感染中具有重要作用。 蛋白質(zhì)的異戊二烯化修飾包括香葉基化(GGPP修飾)和法尼基化(FPP修飾)兩種。它們主要是通過(guò)修飾G蛋白C末端的CaaX基序,如GTPases家族的RAS超家族。這些G蛋白被修飾后,由于存在疏水性而能夠結(jié)合到膜上并激活下游信號(hào)通路如MAPK通路最終發(fā)揮各種生理功能。此外,研究顯示甲羥戊酸途徑抑制劑statin,可以通過(guò)抑制G蛋白的香葉基化和法尼基化進(jìn)而有效的抑制機(jī)體過(guò)度的炎癥反應(yīng)。研究結(jié)果表明蛋白質(zhì)香葉基化和法尼基化修飾之間的比值在不同日齡的大鼠中表現(xiàn)不一樣。這提示它們可能在精子的發(fā)生特別是睪丸組織的免疫調(diào)控中具有重要的功能。 本研究我們主要通過(guò)支持細(xì)胞特異性缺失GGPPS來(lái)確定蛋白質(zhì)的異戊二烯化修飾在支持細(xì)胞調(diào)控免疫反應(yīng)中是否有作用。還有就是這種作用是通過(guò)什么樣的方式實(shí)現(xiàn)的。通過(guò)研究我們發(fā)現(xiàn)： 1.支持細(xì)胞敲除GGPPS改變蛋白質(zhì)異戊二烯化可導(dǎo)致精原細(xì)胞而非支持細(xì)胞在出生后5天出現(xiàn)缺失。 2.支持細(xì)胞缺失GGPPS可導(dǎo)致新生小鼠炎癥因子和趨化因子分泌顯著上升并導(dǎo)致精原細(xì)胞凋亡和巨噬細(xì)胞的管腔侵潤(rùn)。 3.精原細(xì)胞凋亡和睪丸缺陷是由于支持細(xì)胞缺失GGPPS導(dǎo)致MAPK Erk1/2和NF-kB持續(xù)性激活引起。 4.支持細(xì)胞缺失GGPPS導(dǎo)致H-RAS的過(guò)量法尼基化修飾并導(dǎo)致睪丸過(guò)度的炎癥反應(yīng)。 5.腦心肌炎病毒(EMCV)是通過(guò)抑制GGPPS的表達(dá)來(lái)改變蛋白質(zhì)的異戊二烯化修飾并導(dǎo)致的精子發(fā)生障礙。 綜上所述,我們的研究表明支持細(xì)胞中GGPPS通過(guò)調(diào)控蛋白質(zhì)異戊二烯化在幼年小鼠睪丸的發(fā)育過(guò)程中發(fā)揮重要的作用。支持細(xì)胞缺失GGPPS導(dǎo)致新生小鼠支持細(xì)胞中有活性的H-RAS法尼基化修飾明顯升高并促發(fā)睪丸組織的炎癥反應(yīng)。過(guò)量的炎癥反應(yīng)導(dǎo)致新生小鼠精原細(xì)胞缺失并導(dǎo)致不育。這也提示我們,青春期前感染Mumps病毒導(dǎo)致成年不育的原因可能跟異戊二烯化的改變密切相關(guān)。我們的實(shí)驗(yàn)結(jié)果可能為闡釋由于兒童時(shí)期的感染腮腺炎病毒并導(dǎo)致成年不育提供了一種新的機(jī)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.
【學(xué)位授予單位】：南京大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類(lèi)號(hào)】：R725.1

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