本文選題：裸鼴鼠 + 耐低氧　； 參考：《第二軍醫(yī)大學(xué)》2016年碩士論文

【摘要】：研究背景及目的:裸鼴鼠長(zhǎng)期生活于地底下的洞穴環(huán)境中,其周?chē)h(huán)境氧氣濃度極低,只有(10%~15%),其承受低氧環(huán)境的能力是生活于地上的哺乳類(lèi)所不能比擬的。這表明,缺氧造成的損傷或病理改變?cè)谶@種異常耐受低氧環(huán)境的嚙齒類(lèi)中較少或者被徹底清除。然而,對(duì)于這個(gè)物種耐受低氧環(huán)境的機(jī)制我們還不甚了解。在局部缺血性心臟病導(dǎo)致機(jī)體損傷的過(guò)程中,缺氧因素扮演著極其重要的角色。而且,在其他一些致死性損傷疾病的發(fā)展過(guò)程中往往繼發(fā)缺氧。最新數(shù)據(jù)顯示,局部缺血性心臟病在全球范圍內(nèi)特別是中等收入國(guó)家發(fā)病率呈逐年上升的態(tài)勢(shì),其是導(dǎo)致全球性疾病負(fù)擔(dān)的主要原因。對(duì)裸鼴鼠獨(dú)特的耐低氧機(jī)制進(jìn)行研究,將有利于人類(lèi)缺血性疾病的防治及為制定低氧環(huán)境醫(yī)學(xué)保護(hù)措施提供新思路。另外,實(shí)體腫瘤的基本特征之一是局部的低氧微環(huán)境。目前已有的數(shù)據(jù)證實(shí),局部的低氧微環(huán)境不僅是誘導(dǎo)腫瘤惡性轉(zhuǎn)化的始動(dòng)因素,而且其還可以誘導(dǎo)腫瘤細(xì)胞對(duì)放射化療的抵抗。因此,實(shí)體腫瘤局部低氧微環(huán)境被認(rèn)為與多種惡性腫瘤的治療后復(fù)發(fā)、治療效果差和不良預(yù)后密切相關(guān)。因此,闡明裸鼴鼠耐低氧的分子機(jī)制,將為惡性腫瘤的治療提供新線索。研究方法:運(yùn)用低氧艙控制氧氣濃度,急性低氧環(huán)境(5%O2)處理成年(8月齡)裸鼴鼠1h、4h、8h、12h后,提取裸鼴鼠肌肉組織總RNA,運(yùn)用轉(zhuǎn)錄組測(cè)序方法檢測(cè)低氧處理后基因表達(dá)量變化,研究低氧環(huán)境對(duì)裸鼴鼠基因表達(dá)譜的影響。針對(duì)基因表達(dá)水平結(jié)果,篩選低氧處理前后差異表達(dá)的基因,并采用hierarchical聚類(lèi)法對(duì)差異表達(dá)的基因進(jìn)行聚類(lèi),對(duì)各組進(jìn)行GO和KEGG pathway分析。研究差異表達(dá)基因GO功能分類(lèi)及KEGG信號(hào)通路的富集情況。針對(duì)KEGG信號(hào)通路的富集情況,選取一個(gè)顯著差異的信號(hào)通路(MAPK信號(hào)通路)里面的差異表達(dá)基因STMN1、JIP1/MAPK8IP1、JNK3/MAPK10,并根據(jù)GO功能分類(lèi),采用real-time PCR、Western Blotting驗(yàn)證差異基因的表達(dá)。進(jìn)一步針對(duì)差異表達(dá)基因STMN1、JIP1/MAPK8IP1、JNK3/MAPK10,通過(guò)si RNA干擾技術(shù)沉默肌肉成纖維細(xì)胞中STMN1、JIP1/MAPK8IP1、JNK3/MAPK10的表達(dá)。運(yùn)用流式細(xì)胞術(shù)檢測(cè)細(xì)胞周期和凋亡情況,CCK8法檢測(cè)細(xì)胞的增殖活性,研究STMN1、JIP1/MAPK8IP1、JNK3/MAPK10沉默對(duì)細(xì)胞增殖、凋亡和細(xì)胞周期的影響。結(jié)果:差異表達(dá)基因的篩選與對(duì)照組相比,低氧處理1h、4h、8h、12h后裸鼴鼠肌肉組織中基因表達(dá)水平發(fā)生上調(diào)的總數(shù)分別為243個(gè)、304個(gè)、717個(gè)、527個(gè),基因表達(dá)量發(fā)生下調(diào)的基因總數(shù)分別為344個(gè)、332個(gè)、487個(gè)、250個(gè)。在任意情況下與對(duì)照組相比較,表達(dá)水平發(fā)生上調(diào)的基因總數(shù)為1450個(gè),發(fā)生下調(diào)的基因總數(shù)為971個(gè)。采用hierarchical聚類(lèi)法把2337個(gè)差異表達(dá)的基因分成6個(gè)基因功能簇(cluster),顯著地聚集到4個(gè)實(shí)驗(yàn)處理組中。Cluster1、Cluster2、Cluster3、Cluster4、Cluster5、Cluster6中含有的差異基因數(shù)目分別為566個(gè)、566個(gè)、227個(gè)、674個(gè)、108個(gè)、196個(gè)。cluster1中的基因在低氧1h組顯著聚類(lèi),cluster2中的基因在低氧4h組顯著聚類(lèi),cluster4、cluster5中的基因在低氧8h組顯著聚類(lèi),而cluster3、cluster6中的基因在低氧12h組顯著聚類(lèi)。差異表達(dá)基因GO功能富集參照經(jīng)典的基因功能分類(lèi)體系㧟GO功能分類(lèi)體系(Gene ontology),把各個(gè)cluster中的基因進(jìn)行功能的聚集后發(fā)現(xiàn),cluster1、cluster2、cluster3、cluster4、cluster5、cluster6中顯著性富集的GO terms分別有1682個(gè)、1300個(gè)、1384個(gè)、2185個(gè)、637個(gè)、592個(gè)。其中cluster1、cluster2、cluster3、cluster4、cluster5、cluster6中差異最顯著的GO terms分別為解剖結(jié)構(gòu)形態(tài)(anatomical structure morphogenesis)、單一生物過(guò)程(single-organism process)、組織細(xì)胞成分(cellular component organization)、單一生物過(guò)程(single-organism process)、離子轉(zhuǎn)運(yùn)(ion transport)、細(xì)胞-細(xì)胞信號(hào)(cell-cell signaling)。差異表達(dá)基因KEGG信號(hào)通路富集參考KEGG數(shù)據(jù)庫(kù)初步判斷各個(gè)cluster中差異基因顯著性富集信號(hào)通路的情況。cluster1、cluster2、cluster3、cluster4、cluster5、cluster6中差異表達(dá)基因最顯著性富集的信號(hào)通路分別為焦點(diǎn)粘連(Focal adhesion)、擴(kuò)張型心肌病(Dilated cardiomyopathy)、晝夜節(jié)律-哺乳動(dòng)物(Circadian rhythm-mammal)、MAPK信號(hào)通路(MAPK signaling pathway)、甘氨酸,絲氨酸和蘇氨酸代謝(Glycine,serine and threonine metabolism)、II型糖尿病(Type II diabetes mellitus)。差異表達(dá)基因的KEGG信號(hào)通路富集性分析結(jié)果表明,調(diào)控細(xì)胞粘連,細(xì)胞增殖、分化、凋亡以及氨基酸代謝的信號(hào)路徑可能在裸鼴鼠的低氧應(yīng)答反應(yīng)中扮演著重要角色。體外實(shí)驗(yàn)驗(yàn)證差異表達(dá)基因(STMN1、JIP1/MAPK8IP1、JINK3/MAPK10)的表達(dá)低氧培養(yǎng)條件處理24h后,與對(duì)照組相比,裸鼴鼠肌肉成纖維細(xì)胞中STMN1、JIP1/MAPK8IP1、JNK3/MAPK10的表達(dá)水平均表現(xiàn)為顯著上調(diào)。STMN1、JIP1/MAPK8IP1、JNK3/MAPK10表達(dá)的沉默顯著地抑制了裸鼴鼠肌肉成纖維細(xì)胞的增殖活性,誘導(dǎo)細(xì)胞凋亡。并且,沉默STMN1的表達(dá)阻滯裸鼴鼠肌肉成纖維細(xì)胞在G0/G1及S期,沉默JIP1/MAPK8IP1、JNK3/MAPK10的表達(dá)阻斷裸鼴鼠肌肉成纖維細(xì)胞于S期。結(jié)論:運(yùn)用轉(zhuǎn)錄組測(cè)序的方法高通量篩選出裸鼴鼠肌肉組織在低氧處理后2337個(gè)差異表達(dá)的基因,并對(duì)這些差異表達(dá)的基因進(jìn)行了GO功能分類(lèi)和KEGG信號(hào)通路的富集。體外實(shí)驗(yàn)驗(yàn)證了其中三個(gè)差異表達(dá)基因(STMN1、JIP1/MAPK8IP1、JNK3/MAPK10)的表達(dá),從而提示其可能在調(diào)控裸鼴鼠耐受低氧環(huán)境中發(fā)揮重要作用。
[Abstract]:Research background and purpose: the naked mole rats have long lived in the cave environment under the ground where the ambient oxygen concentration is very low, only (10%~15%), and its ability to withstand the low oxygen environment is incomparable to the mammals living on the ground. This indicates that the damage or disease caused by hypoxia is in the rodent with the abnormally tolerable hypoxia environment. It is less or completely eliminated. However, we do not know much about the mechanism of tolerance to hypoxia in this species. Hypoxia plays an important role in the process of local ischemic heart disease causing damage to the body. Moreover, there are often secondary hypoxia in the development of some other fatal injury diseases. The incidence of local ischemic heart disease in the world, especially in middle-income countries, is increasing year by year, which is the main cause of the global disease burden. The study of the unique hypoxia tolerance mechanism for naked mole rats will be beneficial to the prevention and control of human ischemic diseases and to provide new measures for the protection of the hypoxic environment. In addition, one of the basic features of solid tumors is the local hypoxic microenvironment. Current data show that local hypoxia environment is not only a starting factor in inducing malignant transformation of tumor, but also can induce tumor cells to resist radiation chemotherapy. Therefore, local hypoxia microenvironment is considered to be associated with a variety of evil. Therefore, the molecular mechanism of hypoxia tolerance in nude mole rats will provide new clues for the treatment of malignant tumors. Study methods: using hypoxic capsule to control oxygen concentration, acute hypoxia environment (5%O2) treatment of nude mole rats 1H, 4h, 8h, 12h, to extract nude mole rat muscles The change of gene expression after hypoxia treatment was detected by the method of transcription group sequencing, and the influence of hypoxia environment on the gene expression profiles of naked mole rats was studied. According to the results of gene expression, the differentially expressed genes were screened before and after hypoxia treatment, and the differentially expressed genes were clustered by hierarchical clustering method, and GO was used in each group for GO. And KEGG pathway analysis. Study the GO functional classification of differentially expressed genes and the enrichment of KEGG signaling pathways. In view of the enrichment of KEGG signaling pathways, the differential expression of gene STMN1, JIP1/MAPK8IP1, and JNK3/ MAPK10 in a significant differential signal pathway (MAPK signaling pathway) was selected and classified according to GO function. N Blotting verifies the expression of differential genes. Further targeting differential expression genes STMN1, JIP1/MAPK8IP1, JNK3/MAPK10, Si RNA interference technique is used to silence the expression of STMN1, JIP1/MAPK8IP1, JNK3/MAPK10 in muscle fibroblasts. Flow cytometry is used to detect cell cycle and withering, CCK8 method to detect cell proliferation activity, and to study STMN1 The effect of JIP1/MAPK8IP1, JNK3/MAPK10 silence on cell proliferation, apoptosis and cell cycle. Results: the screening of differentially expressed genes was 243, 304, 717, 527, and the gene expression decreased in total gene expression after 1h, 4h, 8h and 12h. There were 344, 332, 487 and 250 respectively. In any case, the total number of genes up regulated by the control group was 1450, and the total number of down regulated genes was 971. 2337 differentially expressed genes were divided into 6 gene power energy clusters (cluster) by hierarchical clustering method, which significantly aggregated to 4 experimental groups. The number of differentially expressed genes in.Cluster1, Cluster2, Cluster3, Cluster4, Cluster5, and Cluster6 were 566, 566, 227, 674, 108, and 196.Cluster1 in the hypoxia 1H group, and the genes in cluster2 were clustered significantly in the hypoxia 4H group, cluster4, and the genes in the low oxygen group were clustering significantly. The genes in the cluster6 group were clustered in the hypoxia 12h group. The differential expression gene GO function enrichment referred to the classical functional classification system of the gene, and the GO functional classification system (Gene ontology), after the aggregation of the genes in each cluster, the significant enrichment of cluster1, cluster2, cluster3, cluster4, cluster5, and cluster5. There are 1682, 1300, 1384, 2185, 637, 592, of which the most distinct GO terms in cluster1, cluster2, cluster3, cluster4, cluster5, cluster6 is the anatomical structure (anatomical structure morphogenesis), and the single biological process (single-organism) On), single biological process (single-organism process), ion transport (ion transport), cell cell signal (cell-cell signaling). Differential expression gene KEGG signaling pathway is enriched by reference KEGG database to determine the status of the difference gene significant enrichment signal pathway in each cluster.Cluster1. The most significant enrichment of differential expression genes in luster6 is focal adhesion (Focal adhesion), dilated cardiomyopathy (Dilated cardiomyopathy), circadian rhythm mammal (Circadian rhythm-mammal), MAPK signaling pathway (MAPK signaling pathway), glycine, serine and threonine metabolism. E metabolism), type II diabetes mellitus (Type II diabetes mellitus). The analysis of the concentration of KEGG signaling pathway of differentially expressed genes shows that the signaling pathways regulating cell adhesion, cell proliferation, differentiation, apoptosis and amino acid metabolism may play an important role in the hypoxia response response in the nude mole rats. In vitro experiments verify the differential expression basis. Compared with the control group, the expression level of STMN1, JIP1/MAPK8IP1, JNK3/MAPK10 in the muscle fibroblasts of the naked mole rat showed a significant increase in.STMN1, JIP1/MAPK8IP1 and JNK3/MAPK10 apparent silence significantly inhibited the muscle fibroblasts of the naked mole rats, compared with the control group because of the low oxygen culture conditions (STMN1, JIP1/MAPK8IP1, JINK3/MAPK10). Proliferation activity and induction of apoptosis, and the expression of silent STMN1 blocking the muscle fibroblasts of nude mole rat at G0/G1 and S phase, silent JIP1/MAPK8IP1, JNK3/MAPK10 expression blocking the muscle fibroblasts of naked mole rats at S stage. Conclusion: the 2337 difference of the muscle tissue of naked mole rat was selected by high throughput screening method by the method of transcriptional sequencing. These differentially expressed genes were expressed by the GO function classification and the enrichment of KEGG signaling pathways. In vitro, three differentially expressed genes (STMN1, JIP1/MAPK8IP1, JNK3/MAPK10) were expressed in vitro, suggesting that it may play an important role in regulating the tolerance to hypoxia in naked mole rats.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類(lèi)號(hào)】：Q78

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10 洪欣;尹昭云;謝印芝;呂永達(dá);;低氧時(shí)肺動(dòng)脈內(nèi)皮細(xì)胞功能變化及其在肺水腫發(fā)生中的作用[A];中國(guó)生理學(xué)會(huì)第六屆全國(guó)青年生理學(xué)工作者學(xué)術(shù)會(huì)議論文摘要[C];2003年

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