增生期糖尿病视网膜病变伴重度黄斑水肿玻璃体蛋白质组学初步研究
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摘要
目的对增生期糖尿病视网膜病变(Proliferative diabetic retinopathy,PDR)伴重度黄斑水肿的玻璃体蛋白质组学变化进行初步研究。
方法在睫状体平坦部穿刺抽取27例PDR伴重度黄斑水肿及9例健康人的玻璃体液,用双向凝胶电泳( 2-DE)的方法得到2-DE图谱,PD Quest7.3.1软件对比图谱,获得差异蛋白点。将差异蛋白点取出、酶解后,用表面增强激光解吸离子化-飞行时间质谱(SELDI-TOF-MS)的方法对玻璃体差异蛋白质进行初步鉴定,得到肽质量指纹图(PMF),采用Mascot和MS-Fit软件进行数据检索,找到差异蛋白;用Western blot行差异蛋白质的蛋白质印迹验证。
结果PDR伴重度黄斑水肿的玻璃体和正常人玻璃体的蛋白质图谱PDQuest软件比较,蛋白点强度相差2倍以上且有统计学意义(P<0.01)的共有30个,其中20个蛋白点上调,10个蛋白点下调。选取上调最明显的10个蛋白点进行质谱分析和数据库的检索及鉴定,其中4个明显差异的蛋白质即11-视黄醇结合蛋白、18-载脂蛋白D、20-载脂蛋白AIV、28-甲状腺激素结合蛋白。
结论初步建立PDR伴重度黄斑水肿的玻璃体的蛋白质2-DE图谱。其蛋白质组发生了改变,本研究发现有四种蛋白质明显增加。
PURPOSE: To identify and analyze proliferative diabetic retinopathy with heavy macular edema-related proteins in the vitreous.
METHODS: The vitreous samples of 27 eyes active proliferative diabetic retinopathy with heavy macular edema patients with 9 normal eyes vitreous samples were analyzed by two-dimensional gel electrophoresis then compared the 2-DE map with PDquest to find the disparation proteins spots. The spots were extracted and been enzymolysis and progressing mass spectrogram identification. Then according the results of Peptide Mass Finger printing(PMF) to find the disparation proteins by searching internet using Mascot and Ms-Fit. One sample of the each group was enrolled to identify disparation proteins by Western blot.
RESULTS: At least 30 proteins were up regulated or down- regulated by over two folds between two groups. 20 protein spots up regulated and 10 down- regulated .Four proteins (apolipoprotein A-IV precursor, Transthyretin precursor, apolipoprotein D , Retinol-binding protein I, cellular) in the 20 spots were expressed significantly differently between the normal and PDR with heavy macular edema patients. The four proteins were up regulated in the diabetic retinopathy with macular edema patients.
CONCLUSIONS: We constructed vitreous protein profiles for proliferative diabetic retinopathy with heavy macular edema patients and identified four candidate proteins believed to be involved in the pathogenesis of proliferative diabetic retinopathy with heavy macular edema.
方法在睫状体平坦部穿刺抽取27例PDR伴重度黄斑水肿及9例健康人的玻璃体液,用双向凝胶电泳( 2-DE)的方法得到2-DE图谱,PD Quest7.3.1软件对比图谱,获得差异蛋白点。将差异蛋白点取出、酶解后,用表面增强激光解吸离子化-飞行时间质谱(SELDI-TOF-MS)的方法对玻璃体差异蛋白质进行初步鉴定,得到肽质量指纹图(PMF),采用Mascot和MS-Fit软件进行数据检索,找到差异蛋白;用Western blot行差异蛋白质的蛋白质印迹验证。
结果PDR伴重度黄斑水肿的玻璃体和正常人玻璃体的蛋白质图谱PDQuest软件比较,蛋白点强度相差2倍以上且有统计学意义(P<0.01)的共有30个,其中20个蛋白点上调,10个蛋白点下调。选取上调最明显的10个蛋白点进行质谱分析和数据库的检索及鉴定,其中4个明显差异的蛋白质即11-视黄醇结合蛋白、18-载脂蛋白D、20-载脂蛋白AIV、28-甲状腺激素结合蛋白。
结论初步建立PDR伴重度黄斑水肿的玻璃体的蛋白质2-DE图谱。其蛋白质组发生了改变,本研究发现有四种蛋白质明显增加。
PURPOSE: To identify and analyze proliferative diabetic retinopathy with heavy macular edema-related proteins in the vitreous.
METHODS: The vitreous samples of 27 eyes active proliferative diabetic retinopathy with heavy macular edema patients with 9 normal eyes vitreous samples were analyzed by two-dimensional gel electrophoresis then compared the 2-DE map with PDquest to find the disparation proteins spots. The spots were extracted and been enzymolysis and progressing mass spectrogram identification. Then according the results of Peptide Mass Finger printing(PMF) to find the disparation proteins by searching internet using Mascot and Ms-Fit. One sample of the each group was enrolled to identify disparation proteins by Western blot.
RESULTS: At least 30 proteins were up regulated or down- regulated by over two folds between two groups. 20 protein spots up regulated and 10 down- regulated .Four proteins (apolipoprotein A-IV precursor, Transthyretin precursor, apolipoprotein D , Retinol-binding protein I, cellular) in the 20 spots were expressed significantly differently between the normal and PDR with heavy macular edema patients. The four proteins were up regulated in the diabetic retinopathy with macular edema patients.
CONCLUSIONS: We constructed vitreous protein profiles for proliferative diabetic retinopathy with heavy macular edema patients and identified four candidate proteins believed to be involved in the pathogenesis of proliferative diabetic retinopathy with heavy macular edema.
引文
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[22] Reixach N,DeechongkiT S, Jiang X, et al.Tissue damage in the myloidoses:Tran- sthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture .[J] Proc Natl Acad Sci USA,2004,101(9):2817-2822
[23] 白小苏,2 型糖尿病家系血清蛋白组学研究[D],重庆医科大学博士学位论文2007,05, 81-82
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[2] 钱小红,贺福初.功能基因组与蛋白质组.蛋白质组学:理论和方法.科学版社,[M]2003:l-15.
[3] Castano EM,Roher AE, Esh CL,et al. Comparative proteomies of elerebrospinalfluid in neuropathologieally eonfirmed Alzheimer,sd1seaseandnon-dementedelderlysubajeets.[J] NeurolRes , 2006 ,28(2):155-163
[4] Kolegraff K,Bostik P,Ansari AA. Charaeterization and role of lentivirus assoeiatedhostproteins. Exp Biol Med(Maywood),2006,231(3): 252-263.
[5] HoehnGT,SuffrediniAF. Proteomies. Crit Care Med,2005,33(12Suppl):s 444-448.
[6] Bresgen M,Baum U, Esser P,et a1.Protein composition of the vitre ousbody in proliferative diabetic retinopathy : An analysis with 2-D electrophoresis.[J]Ophthalmologey,1994,91:758 -762 .
[7] Jiang M,Jia L,Jiang W,et a1.Protein disregulation in red blood cell membranes of type 2diabetic patients.[J]Biochem Biophys Res Commtom,2003,309: 196-200.
[8] Moder M,Kiessling A,Loster H,et a1.The pattern of urinary acylcarnitines determined by electrospray mass spectrometry:a new tool in the diagnosis of diabetes mellitus.Anal Bioanal Chem,2003,375:200-210.
[9] Masayuki O, Karen W, John W. C, et al. Proteomic analysis of vitreous from diabetic macular edema. Experimental Eye Research 81 (2005) 176-182
[10] Bresgen M,Baum U,Esser P,et a1.Protein composition of the vitreous body in proliferative diabetic retinopathy : An analysis with 2D- electrOphoresis.[J]Ophthalmologe,1994:91:758-762.
[11] Toyofumi N, Reiko K,Tsunchiko I ,et al. Catalogue of soluble proteins in the human vitreous humor:comparison between diabetic retinopathy and macular hole. [J]Chromatography B, 776 (2002) 89-100
[12] Lee SH., Park KW., Kim CI.,et al,Proteomics Analysis of Diabetic Retinopathy Vitreous Body ,[J] Invest Ophthalmol Vis Sci 2003;44: E-Abstract 2238
[13] Gerner C, Frohwein U, Gotzmann J. et al. The Fas-induced apoptosis analyzed by high throughput proteome analysis [J]. J Biol Chem. 2000, 275(50): 39018-39026
[14] Blom ML, Green WR, Schachat AP . Diabetic retinopathy: a review. Del Med J. 1994 Jul;66(7):379-88
[15] Miki E , et a1.Diabetes Res Clin Pract ,1994;24(Suppl)s1775 S.H. Lee1, K.W. Park1, C.I. Kim2, Proteomics Analysis of Diabetic Retinopathy Vitreous Body. [J]Invest Ophthalmol Vis Sci 2003;44:
[16] Patel A, Hibberd ML,et al. Chromosome 7q35 and susceptibility to diabetic microvascular complications. [J]J Diabetes Complications,1996;10(2):62-7.
[17] Kraft HG, Lingenhel A, et al. Apolipoprotein(a) kringle IV repeat number predicts risk for coronary heart disease. [J]Arterioscler Thromb ,Vasc Biol,1996;16(6):713-9.
[18] Rabensteiner D, Abrahamian H, Irsigler K et al. ACE gene polymorphism and proliferative retinopathy in type 1 diabetes: results of a case-control study. [J]Diabetes Care,1999;22(9) : 1530-5.
[19] Frederick KB, Thomas CR. Prealbumin: a marker for nutritional evaluation [J]. AM family physician, 2002,65(8): 1575-1578.
[20] Lee W, Choi, HS, Gyrist, J, Brent, R.,et al. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. [J]. Mol Endocrinol 1995.,9, 243–254.
[21] RefaiE,Dekki N, Yang SN, et al. Transthyretin constitutes a functional component pancreatic B-cell stimulus-secretion coupling [J]. Proc Acad Sci USA,2005, 102(47): 17020-17025.
[22] Reixach N,DeechongkiT S, Jiang X, et al.Tissue damage in the myloidoses:Tran- sthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture .[J] Proc Natl Acad Sci USA,2004,101(9):2817-2822
[23] 白小苏,2 型糖尿病家系血清蛋白组学研究[D],重庆医科大学博士学位论文2007,05, 81-82
[24] Noy N,Retinoid-binding proteins: mediators of retinoid action[J].Biochem,2000. Jun 15;348 Pt 3:4 81-95.
[25] Meigs JB, Panhuysen CI, Myers RH, et al. A genome-wide scan for loci linked to plasma levels of glucose and HbAlc in a community-based sample of Caucasian pedigrees: The Framitgsham off spring Staudy [J].Diabetes, 2002, 51(3):833-840.
[26] Duggirals R,Blangero J ,Almasy L, et al. Linkage of type 2 diabetes mellitus and age at onset to a genetic location on chromosome Ioq in Mexican Americans[J] Am J Hum Genet,1999,64(4):1127-1140
[27] Biesalski HK, Nohr D.Importance of vitamin A for lung function and development[J] .Mol Aspects Med,2003,24(6):431-440.
[28] Yang Q,Graham TE,Mody N, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes[J]. Nature 2005,436(7049):356-362.
[29] Timothy E.Graham, Qin Yang, et al .Retinol-binding Protein 4 and insulin Resistance in Lean. Obese and diabetic Subjects[J]. N Engl J Med ,2006,354(24):2552-2563.
[30] Zietz B,Reber T,Oertel M,et a1.Altered function of the hypothalamlc stress axes in patients with moderately active systemic lupus erythematosus.II.Dissociation between and rostenedione,cortisol,or dehydroepiandrosterone and interleukin 6 or tumor necrosis factor .[J]J Rheumatol,2000,27 (4):911-918.
[31] Ken Y, Atsushi M, Hidetoshi Y,et al. Proteome Analysis of Human Vitreous Proteins. [J]Molecular & Cellular Proteomics 2: 2003. 1177-1187.
[32] Gao BB, Chen X, Timothy N, et al. Characterization of the Vitreous Proteome in Diabetes without Diabetic Retinopathy and Diabetes with Proliferative Diabetic Retinopathy. [J] Proteome Res. 2008 Apr 24
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