建立血管内皮细胞敲除DEPTOR基因小鼠模型及鉴定
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摘要
背景:目前关于DEPTOR与血管类疾病的研究较少,在动物体内研究尚未发现,因此建立一种新的血管内皮特异性敲除DEPTOR的小鼠模型对于研究DEPTOR与血管类疾病的关系尤为重要。目的:建立血管内皮细胞敲除DEPTOR基因纯合子小鼠模型,并进行鉴定。方法:Cre小鼠,DEPTOR~(flox/+)雄鼠,均购于美国Jackson实验室;C57野生型小鼠购自华中科技大学。实验方案经中国人民解放军中部战区总医院动物实验伦理委员会批准(批准号:20120034)。选取5只DEPTOR~(flox/+)雄鼠与10只DEPTOR ~(flox/+)雌鼠进行交配,得到基因型为EPTOR~(flox/flox)及DEPTOR~(flox/+)的F1子代小鼠35只,与8只血管内皮细胞特异性表达Tek~+重组酶的Cre小鼠进行交配,一共得到基因型为Tek-Cre~+×DEPTOR~(flox/flox)和DEPTOR~(flox/flox)子代小鼠共65只。采用PCR法进行DEPTOR~(flox)及Cre基因型鉴定,记录Tek-Cre~+×DEPTOR~(flox/flox)小鼠与DEPTOR~(flox/flox)小鼠2月龄的体长及体质量,采用Western blotting法检测2组小鼠肝脏组织DEPTOR蛋白相对表达量,免疫荧光检测两组小鼠血管内皮细胞DEPTOR的表达。结果与结论:①得到基因型为Tek-Cre~+×DEPTOR~(flox/flox)小鼠共25只、DEPTOR~(flox/flox)小鼠共40只,其体长分别为(18.61±1.14),(18.65±1.40) cm,体质量分别为(25.84±1.99),(25.06±2.15) g,二者比较差异均无显著性意义(均P> 0.05);②Tek-Cre~+×DEPTOR~(flox/flox)小鼠与DEPTOR~(flox/flox)小鼠肝脏组织DEPTOR蛋白相对表达量分别为0.28±0.02,0.82±0.04,二者比较P<0.05;③血管内皮细胞DEPTOR阳染率分别为(73.67±2.87)%,(10.33±1.54)%,二者比较P <0.05;④结果证实成功敲除了Tek-Cre~+×DEPTOR~(flox/flox)小鼠的血管内皮细胞的DEPTOR基因;说明成功构建了血管内皮细胞敲除DEPTOR基因纯合子小鼠模型,并经基因型及蛋白组织水平鉴定。
BACKGROUND: There are few studies on DEPTOR and vascular diseases, and no studies have been found in animals. Therefore, the establishment of a new mouse model of vascular endothelial specific knockout DEPTOR is important for studying the relationship between DEPTOR and vascular diseases.OBJECTIVE: To establish and identify a mouse model of vascular endothelial cell knockout DEPTOR gene.METHODS: Cre mice and DEPTOR~(flox/+) mice were purchased from the Jackson Laboratory, and C57 mice were provided by Huazhong University of Science and Technology. The study was approved by the Animal Ethic Committee of General Hospital of Middle Theater Command of Chinese PLA, approval number: 20120034. Five DEPTOR~(flox/+) male mice were selected to mate with 10 DEPTOR~(flox/+) female mice, and 35 F1 progeny mice with genotype of EPTOR~(flox/flox) and DEPTOR~(flox/+) were obtained and mated with 8 vascular endothelial cells specifically expressing Tek recombinase Cre mice. Finally 65 mice with genotypes of Tek-Cre~+ x DEPTOR~(flox/flox) and DEPTOR~(flox/flox) progeny were obtained. The DEPTOR~(flox) and Cre genotypes were identified by PCR, and the body length and body mass of Tek-Cre~+ x DEPTOR~(flox/flox) mice and DEPTOR~(flox/flox) mice at 2 months were recorded. The expression of DEPTOR protein in the mouse liver tissues was detected by western blot assay, and immunofluorescence was used to detect the expression of DEPTOR in the mouse vascular endothelial cells.RESULTS AND CONCLUSION:(1) There were 25 Tek-Cre~+ x DEPTOR~(flox/flox) mice and 40 DEPTOR~(flox/flox) mice, with the body length of(18.61±1.14) and(18.65±1.40) cm, respectively, and body mass of(25.84±1.99) and(25.06±2.15) g, respectively(both P > 0.05).(2) The relative expression level of DEPTOR protein in the Tek-Cre+ x DEPTOR~(flox/flox) mice and DEPTOR~(flox/flox) mice was 0.28±0.02 and 0.82±0.04,respectively(P < 0.05).(3) The number of DEPTOR-positive cell in vascular endothelial cells was 73.67±2.87 and 10.33±1.54, respectively(P< 0.05).(4) The results indicate that DEPTOR gene is successfully knocked out in Tek-Cre~+ x DEPTOR~(flox/flox) mice. The homozygous mouse model of vascular endothelial cell knockout DEPTOR gene is successfully constructed and identified by genotype and protein tissue level.
BACKGROUND: There are few studies on DEPTOR and vascular diseases, and no studies have been found in animals. Therefore, the establishment of a new mouse model of vascular endothelial specific knockout DEPTOR is important for studying the relationship between DEPTOR and vascular diseases.OBJECTIVE: To establish and identify a mouse model of vascular endothelial cell knockout DEPTOR gene.METHODS: Cre mice and DEPTOR~(flox/+) mice were purchased from the Jackson Laboratory, and C57 mice were provided by Huazhong University of Science and Technology. The study was approved by the Animal Ethic Committee of General Hospital of Middle Theater Command of Chinese PLA, approval number: 20120034. Five DEPTOR~(flox/+) male mice were selected to mate with 10 DEPTOR~(flox/+) female mice, and 35 F1 progeny mice with genotype of EPTOR~(flox/flox) and DEPTOR~(flox/+) were obtained and mated with 8 vascular endothelial cells specifically expressing Tek recombinase Cre mice. Finally 65 mice with genotypes of Tek-Cre~+ x DEPTOR~(flox/flox) and DEPTOR~(flox/flox) progeny were obtained. The DEPTOR~(flox) and Cre genotypes were identified by PCR, and the body length and body mass of Tek-Cre~+ x DEPTOR~(flox/flox) mice and DEPTOR~(flox/flox) mice at 2 months were recorded. The expression of DEPTOR protein in the mouse liver tissues was detected by western blot assay, and immunofluorescence was used to detect the expression of DEPTOR in the mouse vascular endothelial cells.RESULTS AND CONCLUSION:(1) There were 25 Tek-Cre~+ x DEPTOR~(flox/flox) mice and 40 DEPTOR~(flox/flox) mice, with the body length of(18.61±1.14) and(18.65±1.40) cm, respectively, and body mass of(25.84±1.99) and(25.06±2.15) g, respectively(both P > 0.05).(2) The relative expression level of DEPTOR protein in the Tek-Cre+ x DEPTOR~(flox/flox) mice and DEPTOR~(flox/flox) mice was 0.28±0.02 and 0.82±0.04,respectively(P < 0.05).(3) The number of DEPTOR-positive cell in vascular endothelial cells was 73.67±2.87 and 10.33±1.54, respectively(P< 0.05).(4) The results indicate that DEPTOR gene is successfully knocked out in Tek-Cre~+ x DEPTOR~(flox/flox) mice. The homozygous mouse model of vascular endothelial cell knockout DEPTOR gene is successfully constructed and identified by genotype and protein tissue level.
引文
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[2]Kim B, Lee Y, Yoo H, et al. Anti-angiogenic activity of thienopyridine derivative LCB03-0110 by targeting VEGFR-2and JAK/STAT3 Signalling. Exp Dermatol. 2015;24(7):503-509.
[3]王丽,李录英,陆齐,等. CD73在乳腺癌血管新生中的作用[J].中国病理生理杂志,2015,12(10):1843.
[4]Li S,Haigh K,Haigh JJ,et al.Endothelial VEGF sculpts cortical cytoarchitecture.J Neurosci.2013;33(37):14809-14815.
[5]江克华,董自强,宋兴福,等.PI3K/PTEN信号通路与肿瘤血管形成关系的研究进展[J].实用医学杂志,2011,27(22):4169-4170.
[6]李景,付焱,肖光雄,等.源于乳腺癌干细胞的内皮细胞参与肿瘤血管形成的实验研究[J].医学研究生学报, 2016,29(11):1191-1196.
[7]陈银涛,于秉治,武迪迪. PI3K/Akt/mTOR信号通路及临床相关肿瘤抑制剂[J].中国生物化学与分子生物学报, 2014,30(10):949-956.
[8]廖明娟,陈红风.PI3K/Akt/mTOR信号通路抑制剂在乳腺癌中的研究进展[J].中华肿瘤防治杂志,2012,19(3):230-234.
[9]王法斌,李京波.他汀类药物对血管形成的作用及分子机制[J].实用医学杂志,2012,28(23):4018-4020.
[10]许小兵,郭美霞,金鑫鑫,等.塞来昔布抑制血管内皮细胞迁移的实验研究[J].医学研究生学报,2017,30(6):601-605.
[11]王宇霆,周海燕,吕小翠.白藜芦醇对过氧化氢氧化应激损伤人脐静脉血管内皮细胞的保护作用[J].中华医学杂志, 2013,93(15):1174-1177.
[12]马丽娜,陈北冬,赵艳阳,等.银杏内酯B对内皮细胞的保护作用及分子机制研究[J].中国药理学通报,2013,29(2):189-193.
[13]Ghosh CC, Mukherjee A, David S, et al. Angiopoietin-1Requires Oxidant Signaling through p47phox to Promote Endothelial Barrier Defense.PLoS One. 2015;10(3):e119577.
[14]周政荣,丁丽娜.冠心病合并糖尿病应用奥美沙坦酯对患者血管内皮细胞功能的影响作用[J].北方药学,2018,15(11):29-30.
[15]王志钢,吴应积,旭日干. mTOR信号通路与细胞生长调控[J].生物物理学报,2007,23(5):333-342.
[16]高阳,田树旭,常小丽,等.雷帕霉素靶蛋白的蛋白信号通路及其与代谢性疾病相关性[J].医学研究生学报,2010,23(2):196-201.
[17]Chung AS,Lee J, Ferrara N. Targeting the tumour vasculature:insights from physiological angiogenesis. Nat Rev Cancer.2010;10(7):505-514.
[18]Zeng Q,Wu Z,Duan H,et al.Impaired tumor angiogenesis and VEGF-induced pathway in endothelial CD146 knockout mice.Protein Cell.2014;5(6):445-456.
[19]Huang B,Wang Y,Wang W,et al. mTORC1 Prevents Preosteoblast Differentiation through the Notch Signaling Pathway. PLOS Genetics.2015;11(8):400-426.
[20]Ma A, Wang L, Gao Y, et al. Tsc1 deficiency-mediated mTOR hyperactivation in vascular endothelial cells causes angiogenesis defects and embryonic lethality. Human Molecular Genetics.2014,23(3):693-705.
[21]Duan S, Shafi JRS, Kuchay S, et al. mTOR Generates an Auto-Amplification Loop by Triggering the bTrCP-and CK1a-Dependent Degradation of DEPTOR. 2011:44:317-324.
[22]Zhan JK, Wang YJ, Wang Y, et al. Adiponectin attenuates the osteoblastic differentiation of vascular smooth muscle cells through the AMPK/mTOR pathway. Exp Cell Res.2014;323(2):352-358.
[23]Laplante M, Horvat S, Festuccia WT, et al. DEPTOR Cell-Autonomously Promotes Adipogenesis, and Its Expression Is Associated with Obesity. Cell Metab. 2012;16(2):202-212.
[24]Kazi AA,Hong-Brown L,Lang SM, et al. Deptor knockdown enhances mTOR Activity and protein synthesis in myocytes and ameliorates disuse muscle atrophy. Mol Med.2011;17(9-10):925-936.
[25]Bruneau S,Nakayama H,Woda CB,et al.DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses. Blood. 2013;122(10):1833-1842.
[26]Liu M, Wilk SA, Wang A, et al. Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR.J Biol Chem.2010;285(47):36387-36394.
[27]赖舒畅,邱鸿,王肖,等.条件性胰岛β细胞DEPTOR基因敲除小鼠构建及鉴定[J].实用医学杂志,2018,34(4):552-555.
[28]王志蕊,刘西梅,周荆荣,等. Cre-LoxP重组系统删除内源性选择标记基因的效能评价[J].中国生物化学与分子生物学报, 2014,30(2):194-201.
[29]吴壮,徐军.Cre/Loxp位点重组酶系统在疾病动物模型建立中的应用[J].国外医学(呼吸系统分册),2004,24(4):254-256.
[30]任荣荣,王英伟. Cre/Loxp系统的应用及进展[J].广州医学院学报,2008,36(2):78-80.
[31]Hong J,Liu R,Chen L,et al. Conditional knockout of tissue factor pathway inhibitor 2 in vascular endothelial cells accelerates atherosclerotic plaque development in mice.Thromb Res.2016;137:148-156.
[32]桑璐,郭英,任立明,等.利用Cre/lox重组系统在转基因动物中筛选高效表达外源基因的"友好"基因座[J].高技术通讯,2004,14(12):43-49.
[33]Campochiaro PA, Sophie R, Tolentino M, et al. Treatment of diabetic macular edema with an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates tie2.Ophthalmology.2015;122(3):545-554.
[34]Sarkar K, Rey S, Zhang X, et al. Tie2-dependent knockout of HIF-1 impairs burn wound vascularization and homing of bone marrow-derived angiogenic cells. Cardiovascular Res.2011;93(1):162-169.
[35]Kawakami Y, Ii M, Matsumoto T, et al. SDF-1/CXCR4 Axis in Tie2-Lineage Cells Including Endothelial Progenitor Cells Contributes to Bone Fracture Healing. J Bone Miner Res.2015;30(1):95-105.
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