Hostname: page-component-78c5997874-fbnjt Total loading time: 0 Render date: 2024-11-16T18:05:40.529Z Has data issue: false hasContentIssue false
  • English
  • Français

Application of multiplex immunoassay technology to investigations of ocular disease

Published online by Cambridge University Press:  31 August 2016

Valerie Sloane Jones ,
Jian Wu ,
Si-Wei Zhu  and
Ruo-Pan Huang
Valerie Sloane Jones
Affiliation:
Raybiotech, Inc., Norcross, GA, USA
Jian Wu
Affiliation:
The Affiliated third Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangdong, China
Si-Wei Zhu
Affiliation:
RayBiotech, Inc., Guangzhou, China
Ruo-Pan Huang*
Affiliation:
Raybiotech, Inc., Norcross, GA, USA RayBiotech, Inc., Guangzhou, China South China Biochip Research Center, Guangzhou, China
*
*Corresponding author: Ruo-Pan Huang, Raybiotech, Inc, 3607 Parkway Lane, Suite 100, Norcross, GA 30092, USA. E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Eye-derived fluids, including tears, aqueous humour and vitreous humour often contain molecular signatures of ocular disease states. These signatures can be composed of cytokines, chemokines, growth factors, proteases and soluble receptors. However, the small quantities (<10 µl) of these fluids severely limit the detection of these proteins by traditional enzyme-linked immunosorbent assay or Western blot. To maximise the amount of information generated from the analysis of these specimens, many researchers have employed multiplex immunoassay technologies for profiling the expression or modification of multiple proteins from minute sample volumes.

Type
Review
Information
Expert Reviews in Molecular Medicine , Volume 18 , 2016 , e15
Copyright
Copyright © Cambridge University Press 2016 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Broux, B. et al. (2012) CX(3)CR1 drives cytotoxic CD4(+)CD28(−) T cells into the brain of multiple sclerosis patients. Journal of Autoimmunity 38, 10-19 CrossRefGoogle Scholar
2. Kaplin, A.I. et al. (2005) IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis. Journal of Clinical Investigation 115, 2731-2741 CrossRefGoogle ScholarPubMed
3. Ichikawa, T. et al. (2007) Possible impact of salivary influence on cytokine analysis in exhaled breath condensate. Analytical Chemistry Insights 2, 85-92 Google Scholar
4. Tatarakis, N. et al. (2014) Clinical, microbiological, and salivary biomarker profiles of dental implant patients with type 2 diabetes. Clinical Oral Implants Research 25, 803-812 CrossRefGoogle ScholarPubMed
5. Kverka, M. et al. (2007) Cytokine profiling in human colostrum and milk by protein array. Clinical Chemistry 53, 955-962 Google Scholar
6. Benabid, R. et al. (2012) Neutrophil elastase modulates cytokine expression: contribution to host defense against Pseudomonas aeruginosa-induced pneumonia. Journal of Biological Chemistry 287, 34883-34894 Google Scholar
7. Honko, A.N. and Mizel, S.B. (2004) Mucosal administration of flagellin induces innate immunity in the mouse lung. Infection and Immunity 72, 6676-6679 Google Scholar
8. Wilson, J.J. et al. (2015) Antibody arrays in biomarker discovery. Advances in Clinical Chemistry 69, 255-324 Google Scholar
9. Chowdhury, U.R. et al. (2010) Proteome analysis of human aqueous humor. Investigative Ophthalmology & Visual Science 51, 4921-4931 Google Scholar
10. Schwartzman, M.L. et al. (2010) Profile of lipid and protein autacoids in diabetic vitreous correlates with the progression of diabetic retinopathy. Diabetes 59, 1780-1788 CrossRefGoogle ScholarPubMed
11. Zhou, L. et al. (2012) In-depth analysis of the human tear proteome. Journal of Proteomics 75, 3877-3885 Google Scholar
12. Tiffany, J.M. (2008) The normal tear film. Developments in Ophthalmology 41, 1-20 Google Scholar
13. Zhou, L. and Beuerman, R.W. (2012) Tear analysis in ocular surface diseases. Progress in Retinal and Eye Research 31, 527-550 CrossRefGoogle ScholarPubMed
14. Fung, K., Morris, C. and Duncan, M. (2002) Mass spectrometric techniques applied to the analysis of human tears: a focus on the peptide and protein constituents. Advances in Experimental Medicine and Biology 506(Pt A), 601-605 Google Scholar
15. Sullivan, D.A., Dartt, D.A. and Meneray, M.A. (2012) Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2: Basic Science and Clinical Relevance, Vol. 438. Springer Science & Business Media, New York, NY Google Scholar
16. Pieragostino, D. et al. (2015) Unraveling the molecular repertoire of tears as a source of biomarkers: beyond ocular diseases. Proteomics – Clinical Applications 9, 169-186 Google Scholar
17. Sack, R.A. et al. (2005) Membrane array characterization of 80 chemokines, cytokines, and growth factors in open- and closed-eye tears: angiogenin and other defense system constituents. Investigative Ophthalmology & Visual Science 46, 1228-1238 Google Scholar
18. Goren, M.B. (1997) Neural stimulation of lactoferrin and epidermal growth factor secretion by the lacrimal gland. Cornea 16, 501-502 Google Scholar
19. Thakur, A., Willcox, M.D. and Stapleton, F. (1998) The proinflammatory cytokines and arachidonic acid metabolites in human overnight tears: homeostatic mechanisms. Journal of Clinical Immunology 18, 61-70 Google Scholar
20. Hooper, L.V. et al. (2003) Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nature Immunology 4, 269-273 Google Scholar
21. Sack, R.A. et al. (2000) Towards a closed eye model of the pre-ocular tear layer. Progress in Retinal and Eye Research 19, 649-668 Google Scholar
22. Sack, R. et al. (2007) Antibody array characterization of inflammatory mediators in allergic and normal tears in the open and closed eye environments. Experimental Eye Research 85, 528-538 Google Scholar
23. Mulvenna, I. et al. (2000) Low molecular weight analysis of tears using matrix assisted laser desorption ionization-time of flight mass spectrometry. Clinical & Experimental Ophthalmology 28, 205-207 Google Scholar
24. Shoji, J., Inada, N. and Sawa, M. (2006) Antibody array-generated cytokine profiles of tears of patients with vernal keratoconjunctivitis or giant papillary conjunctivitis. Japanese Journal of Ophthalmology 50, 195-204 Google Scholar
25. Kokuludag, A. et al. (2001) Serum soluble tumor necrosis factor receptor levels in patients with seasonal allergic rhinitis. Journal of Investigational Allergology & Clinical Immunology 11, 46-48 Google Scholar
26. Benson, M. et al. (2000) Increase of the soluble IL-4 receptor (IL-4sR) and positive correlation between IL-4sR and IgE in nasal fluids from school children with allergic rhinitis. Allergy and Asthma Proceedings 21, 89-95 Google Scholar
27. Cheung, I.M., McGhee, C.N. and Sherwin, T. (2013) A new perspective on the pathobiology of keratoconus: interplay of stromal wound healing and reactive species-associated processes. Clinical & Experimental Optometry 96, 188-196 Google Scholar
28. Kenney, M.C. et al. (2005) Increased levels of catalase and cathepsin V/L2 but decreased TIMP-1 in keratoconus corneas: evidence that oxidative stress plays a role in this disorder. Investigative Ophthalmology & Visual Science 46, 823-832 Google Scholar
29. Pannebaker, C., Chandler, H.L. and Nichols, J.J. (2010) Tear proteomics in keratoconus. Molecular Vision 16, 1949-1957 Google Scholar
30. Seppala, H.P. et al. (2006) EMMPRIN and MMP-1 in keratoconus. Cornea 25, 325-330 CrossRefGoogle ScholarPubMed
31. Collier, S.A. (2001) Is the corneal degradation in keratoconus caused by matrix-metalloproteinases? Clinical & Experimental Ophthalmology 29, 340-344 Google Scholar
32. Abalain, J.H. et al. (2000) Levels of collagen degradation products (telopeptides) in the tear film of patients with keratoconus. Cornea 19, 474-476 Google Scholar
33. Cheung, I.M., McGhee, C. and Sherwin, T. (2014) Deficient repair regulatory response to injury in keratoconic stromal cells. Clinical & Experimental Optometry 97, 234-239 Google Scholar
34. Semeraro, F. et al. (2015) Diabetic retinopathy: vascular and inflammatory disease. Journal of Diabetes Research 2015, 582060 Google Scholar
35. Maier, R. et al. (2006) Application of multiplex cytometric bead array technology for the measurement of angiogenic factors in the vitreous. Molecular Vision 12, 1143-1147 Google Scholar
36. Maier, R. et al. (2008) Multiplex bead analysis of vitreous and serum concentrations of inflammatory and proangiogenic factors in diabetic patients. Molecular Vision 14, 637-643 Google Scholar
37. Nagata, K. et al. (2012) Simultaneous analysis of multiple cytokines in the vitreous of patients with sarcoid uveitis. Investigative Ophthalmology & Visual Science 53, 3827-3833 Google Scholar
38. Sato, T. et al. (2009) Simultaneous analyses of vitreous levels of 27 cytokines in eyes with retinopathy of prematurity. Ophthalmology 116, 2165-2169 Google Scholar
39. Aiello, L.P. et al. (1998) Diabetic retinopathy. Diabetes Care 21, 143-156 Google Scholar
40. Aronson, D. (2008) Hyperglycemia and the pathobiology of diabetic complications. Advances in Cardiology 45, 1-16 Google Scholar
41. Kowluru, R.A. (2005) Diabetic retinopathy: mitochondrial dysfunction and retinal capillary cell death. Antioxidants & Redox Signaling 7, 1581-1587 Google Scholar
42. Kowluru, R.A., Tang, J. and Kern, T.S. (2001) Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 50, 1938-1942 Google Scholar
43. Capeans, C. et al. (1998) C-C chemokines in the vitreous of patients with proliferative vitreoretinopathy and proliferative diabetic retinopathy. Retina 18, 546-550 Google Scholar
44. Elner, S.G. et al. (1995) Cytokines in proliferative diabetic retinopathy and proliferative vitreoretinopathy. Current Eye Research 14, 1045-1053 Google Scholar
45. Hernandez, C. et al. (2005) Interleukin-8, monocyte chemoattractant protein-1 and IL-10 in the vitreous fluid of patients with proliferative diabetic retinopathy. Diabetic Medicine 22, 719-722 Google Scholar
46. Mitamura, Y. et al. (2001) Monocyte chemotactic protein-1 in the vitreous of patients with proliferative diabetic retinopathy. Ophthalmologica 215, 415-418 CrossRefGoogle ScholarPubMed
47. Canataroglu, H. et al. (2005) Interleukin (IL)-6, interleukin (IL)-8 levels and cellular composition of the vitreous humor in proliferative diabetic retinopathy, proliferative vitreoretinopathy, and traumatic proliferative vitreoretinopathy. Ocular Immunology and Inflammation 13, 375-381 CrossRefGoogle ScholarPubMed
48. Yuuki, T. et al. (2001) Inflammatory cytokines in vitreous fluid and serum of patients with diabetic vitreoretinopathy. Journal of Diabetes and Its Complications 15, 257-259 Google Scholar
49. Aiello, L.P. et al. (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. New England Journal of Medicine 331, 1480-1487 Google Scholar
50. Wang, J. et al. (2014) Vitreous and plasma VEGF levels as predictive factors in the progression of proliferative diabetic retinopathy after vitrectomy. PLoS ONE 9, e110531 Google ScholarPubMed
51. Banerjee, S. et al. (2007) Multiplex bead analysis of vitreous humor of patients with vitreoretinal disorders. Investigative Ophthalmology & Visual Science 48, 2203-2207 Google Scholar
52. Aiello, L.P. et al. (1995) Hypoxic regulation of vascular endothelial growth factor in retinal cells. Archives of Ophthalmology 113, 1538-1544 Google Scholar
53. Itakura, H. et al. (2004) Persistent secretion of vascular endothelial growth factor into the vitreous cavity in proliferative diabetic retinopathy after vitrectomy. Ophthalmology 111, 1880-1884 Google Scholar
54. Murata, T. et al. (1995) Vascular endothelial growth factor plays a role in hyperpermeability of diabetic retinal vessels. Ophthalmic Research 27, 48-52 Google Scholar
55. Reverter, J.L. et al. (2009) Tyrosine phosphorylation of vitreous inflammatory and angiogenic peptides and proteins in diabetic retinopathy. Investigative Ophthalmology & Visual Science 50, 1378-1382 Google Scholar
56. Wakefield, D. and Chang, J.H. (2005) Epidemiology of uveitis. International Ophthalmology Clinics 45, 1-13 Google Scholar
57. Bodaghi, B. et al. (2012) Toxoplasmosis: new challenges for an old disease. Eye (London) 26, 241-244 Google Scholar
58. Gupta, V., Gupta, A. and Rao, N.A. (2007) Intraocular tuberculosis – an update. Survey of Ophthalmology 52, 561-587 Google Scholar
59. Hunt, L. and Knott, V. (2016) Serious and common sequelae after Ebola virus infection. The Lancet Infectious Diseases 16, 270-271 Google Scholar
60. Varkey, J.B. et al. (2015) Persistence of Ebola virus in ocular fluid during convalescence. The New England Journal of Medicine 372, 2423-2427 CrossRefGoogle ScholarPubMed
61. Perez, V.L. and Caspi, R.R. (2015) Immune mechanisms in inflammatory and degenerative eye disease. Trends in Immunology 36, 354-363 Google Scholar
62. Valentincic, N.V. et al. (2011) Intraocular and serum cytokine profiles in patients with intermediate uveitis. Molecular Vision 17, 2003-2010 Google Scholar
63. Chen, W. et al. (2015) Cytokine expression profile in aqueous humor and sera of patients with acute anterior uveitis. Current Molecular Medicine 15, 543-549 CrossRefGoogle ScholarPubMed
64. Kalariya, N.M. et al. (2010) Prevention of endotoxin-induced uveitis in rats by plant sterol guggulsterone. Investigative Ophthalmology & Visual Science 51, 5105-5113 Google Scholar
65. Takeda, A., Sonoda, K.-H. and Ishibashi, T. (2013) Regulation of Th1 and Th17 cell differentiation in uveitis. Inflammation and Regeneration 33, 261-268 Google Scholar
66. Lee, R.W. et al. (2014) Autoimmune and autoinflammatory mechanisms in uveitis. Seminars in Immunopathology 36, 581-594 Google Scholar
67. Ooi, K.G. et al. (2006) Cytokines and chemokines in uveitis: is there a correlation with clinical phenotype? Clinical Medicine & Research 4, 294-309 Google Scholar
68. Curnow, S.J. et al. (2005) Multiplex bead immunoassay analysis of aqueous humor reveals distinct cytokine profiles in uveitis. Investigative Ophthalmology & Visual Science 46, 4251-4259 Google Scholar
69. Yoshimura, T. et al. (2009) Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis. “Rheumatology (Oxford, England)” 48, 347-354 Google Scholar
70. Lahmar, I. et al. (2009) Cytokine profiles in toxoplasmic and viral uveitis. Journal of Infectious Diseases 199, 1239-1249 Google Scholar
71. Tezel, G. (2011) The immune response in glaucoma: a perspective on the roles of oxidative stress. Experimental Eye Research 93, 178-186 Google Scholar
72. Tezel, G. and A.P.O.R.I.C.W.G. Fourth (2009) The role of glia, mitochondria, and the immune system in glaucoma. Investigative Ophthalmology & Visual Science 50, 1001-1012 Google Scholar
73. Kuchtey, J. et al. (2010) Multiplex cytokine analysis reveals elevated concentration of interleukin-8 in glaucomatous aqueous humor. Investigative Ophthalmology & Visual Science 51, 6441-6447 Google Scholar
74. Thirumangalakudi, L. et al. (2007) IL-8 induces expression of matrix metalloproteinases, cell cycle and pro-apoptotic proteins, and cell death in cultured neurons. Journal of Alzheimer's Disease 11, 305-311 Google Scholar
75. Birke, M.T. et al. (2010) Changes of osteopontin in the aqueous humor of the DBA2/J glaucoma model correlated with optic nerve and RGC degenerations. Investigative Ophthalmology & Visual Science 51, 5759-5767 Google Scholar
76. Chang, B. et al. (1999) Interacting loci cause severe iris atrophy and glaucoma in DBA/2J mice. Nature Genetics 21, 405-409 Google Scholar
77. Neumann, C. et al. (2014) Osteopontin is induced by TGF-beta2 and regulates metabolic cell activity in cultured human optic nerve head astrocytes. PLoS ONE 9, e92762 Google Scholar
78. Del Rio, P. et al. (2011) GDNF-induced osteopontin from Muller glial cells promotes photoreceptor survival in the Pde6brd1 mouse model of retinal degeneration. Glia 59, 821-832 Google Scholar
79. Cha, D.M. et al. (2013) Comparative analysis of aqueous humor cytokine levels between patients with exudative age-related macular degeneration and normal controls. Investigative Ophthalmology & Visual Science 54, 7038-7044 CrossRefGoogle ScholarPubMed
80. Spraul, C.W. et al. (2002) Octreotide inhibits growth factor-induced bovine choriocapillary endothelial cells in vitro. Graefe's Archive for Clinical and Experimental Ophthalmology 240, 227-231 Google Scholar
81. Cheung, C.M. et al. (2012) Comparison of aqueous humor cytokine and chemokine levels in diabetic patients with and without retinopathy. Molecular Vision 18, 830-837 Google Scholar
82. Altshuler, D., Daly, M.J. and Lander, E.S. (2008) Genetic mapping in human disease. Science 322, 881-888 Google Scholar
83. Mizuki, N. et al. (2010) Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet's disease susceptibility loci. Nature Genetics 42, 703-706 Google Scholar
84. Remmers, E.F. et al. (2010) Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease. Nature Genetics 42, 698-702 CrossRefGoogle ScholarPubMed
85. Kirino, Y. et al. (2013) Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1. Nature Genetics 45, 202-207 Google Scholar
86. Xavier, J.M. et al. (2012) Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behcet's disease. Arthritis and Rheumatism 64, 2761-2772 Google Scholar
87. Abraham, C. and Cho, J. (2009) Interleukin-23/Th17 pathways and inflammatory bowel disease. Inflammatory Bowel Diseases 15, 1090-1100 Google Scholar
88. Di Cesare, A., Di Meglio, P. and Nestle, F.O. (2009) The IL-23/Th17 axis in the immunopathogenesis of psoriasis. Journal of Investigative Dermatology 129, 1339-1350 Google Scholar
89. Merida, S. et al. (2015) New immunosuppressive therapies in uveitis treatment. International Journal Molecular Science 16, 18778-18795 Google Scholar
90. Klein, R.J. et al. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308, 385-389 Google Scholar
91. Edwards, A.O. et al. (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308, 421-424 Google Scholar
92. Haines, J.L. et al. (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308, 419-421 Google Scholar
93. Rivera, A. et al. (2005) Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Human Molecular Genetics 14, 3227-3236 Google Scholar
94. Dewan, A. et al. (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314, 989-992 Google Scholar
95. Tong, Y. et al. (2010) LOC387715/HTRA1 gene polymorphisms and susceptibility to age-related macular degeneration: a HuGE review and meta-analysis. Molecular Vision 16, 1958-1981 Google Scholar
96. Fritsche, L.G. et al. (2013) Seven new loci associated with age-related macular degeneration. Nature Genetics 45, 433-439, 439e1-2Google Scholar
97. Arakawa, S. et al. (2011) Genome-wide association study identifies two susceptibility loci for exudative age-related macular degeneration in the Japanese population. Nature Genetics 43, 1001-1004 Google Scholar
98. Nakano, M. et al. (2009) Three susceptible loci associated with primary open-angle glaucoma identified by genome-wide association study in a Japanese population. Proceedings of the National Academy of Sciences of the United States of America 106, 12838-12842 Google Scholar
99. Rao, K.N., Kaur, I. and Chakrabarti, S. (2009) Lack of association of three primary open-angle glaucoma-susceptible loci with primary glaucomas in an Indian population. Proceedings of the National Academy of Sciences of the United States of America 106, E125-E126; author reply E127Google Scholar
100. Thorleifsson, G. et al. (2010) Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nature Genetics 42, 906-909 Google Scholar
101. Burdon, K.P. et al. (2011) Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nature Genetics 43, 574-578 Google Scholar
102. Baratz, K.H. et al. (2010) E2-2 protein and Fuchs's corneal dystrophy. New England Journal of Medicine 363, 1016-1024 Google Scholar
103. Li, Y.J. et al. (2011) Replication of TCF4 through association and linkage studies in late-onset fuchs endothelial corneal dystrophy. PLoS ONE 6, e18044Google Scholar
104. Thalamuthu, A. et al. (2011) Association of TCF4 gene polymorphisms with Fuchs’ corneal dystrophy in the Chinese. Investigative Ophthalmology & Visual Science 52, 5573-5578 Google Scholar
105. Li, X.H. et al. (2012) A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries. Human Molecular Genetics 21, 421-429 Google Scholar
106. Burdon, K.P. et al. (2011) Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus. Investigative Ophthalmology & Visual Science 52, 8514-8519 Google Scholar
107. Gu, J. et al. (2009) Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers. Molecular & Cellular Proteomics 8, 1338-1349 Google Scholar
108. Nguyen, T.T. et al. (2009) Inflammatory, hemostatic, and other novel biomarkers for diabetic retinopathy the multi-ethnic study of atherosclerosis. Diabetes Care 32, 1704-1709 Google Scholar
109. Hirano, T. et al. (2012) A case of Behcet's disease treated with a humanized anti-interleukin-6 receptor antibody, tocilizumab. Modern Rheumatology 22, 298-302 CrossRefGoogle ScholarPubMed
110. Adan, A. et al. (2013) Tocilizumab treatment for refractory uveitis-related cystoid macular edema. Graefe's Archive for Clinical and Experimental Ophthalmology 251, 2627-2632 Google Scholar
111. Sfikakis, P.P. et al. (2004) Infliximab for recurrent, sight-threatening ocular inflammation in Adamantiades-Behcet disease. Annals of Internal Medicine 140, 404-406 Google Scholar
112. Bravo-Ljubetic, L. et al. (2013) Adalimumab therapy for refractory childhood uveitis. Journal of AAPOS 17, 456-459 Google Scholar
113. Simonini, G. et al. (2013) Superior efficacy of Adalimumab in treating childhood refractory chronic uveitis when used as first biologic modifier drug: Adalimumab as starting anti-TNF-alpha therapy in childhood chronic uveitis. Pediatric Rheumatology Online Journal 11, 16 Google Scholar
114. Gul, A. et al. (2012) Interleukin-1beta-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behcet's disease: an open-label pilot study. Annals of the Rheumatic Diseases 71, 563-566 Google Scholar
115. Ferrara, N., Gerber, H.P. and LeCouter, J. (2003) The biology of VEGF and its receptors. Nature Medicine 9, 669-676 Google Scholar
116. Hellström, A. et al. (2002) IGF-I is critical for normal vascularization of the human retina. The Journal of Clinical Endocrinology & Metabolism 87, 3413-3416 Google Scholar
117. Jacobo, S.M. and Kazlauskas, A. (2015) Insulin-like growth factor 1 (IGF-1) stabilizes nascent blood vessels. Journal of Biological Chemistry 290, 6349-6360 Google Scholar
118. Rajappa, M., Saxena, P. and Kaur, J. (2010) Ocular angiogenesis: mechanisms and recent advances in therapy. Advances in Clinical Chemistry 50, 103-121 Google Scholar
119. Sene, A., Chin-Yee, D. and Apte, R.S. (2015) Seeing through VEGF: innate and adaptive immunity in pathological angiogenesis in the eye. Trends in Molecular Medicine 21, 43-51 Google Scholar
120. Doukas, J. et al. (2008) Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. Journal of Cellular Physiology 216, 29-37 Google Scholar
121. Dalal, M. et al. (2013) Subconjunctival Palomid 529 in the treatment of neovascular age-related macular degeneration. Graefe's Archive for Clinical and Experimental Ophthalmology 251, 2705-2709 Google Scholar
122. Kaiser, P.K. (2013) Emerging therapies for neovascular age-related macular degeneration: drugs in the pipeline. Ophthalmology 120(5 Suppl), S11-S15 Google Scholar
123. Prendes, M.A. et al. (2013) The role of transforming growth factor β in glaucoma and the therapeutic implications. British Journal of Ophthalmology 97, 680-686 Google Scholar
124. Wordinger, R.J., Sharma, T. and Clark, A.F. (2014) The role of TGF-β2 and bone morphogenetic proteins in the trabecular meshwork and glaucoma. Journal of Ocular Pharmacology and Therapeutics 30, 154-162 Google Scholar
125. Barabasi, A.-L. and Oltvai, Z.N. (2004) Network biology: understanding the cell's functional organization. Nature Reviews Genetics 5, 101-113 Google Scholar
126. Copeland, S., Siddiqui, J. and Remick, D. (2004) Direct comparison of traditional ELISAs and membrane protein arrays for detection and quantification of human cytokines. Journal of Immunological Methods 284, 99-106 Google Scholar
127. Ingvarsson, J. et al. (2006) One-step fractionation of complex proteomes enables detection of low abundant analytes using antibody-based microarrays. Journal of Proteome Research 5, 170-176 Google Scholar
128. Chang, L. et al. (2012) Single molecule enzyme-linked immunosorbent assays: theoretical considerations. Journal of Immunological Methods 378, 102-115 Google Scholar
129. Rissin, D.M. et al. (2010) Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nature Biotechnology 28, 595-599 Google Scholar
130. Fischer, S.K. et al. (2015) Emerging technologies to increase ligand binding assay sensitivity. The AAPS Journal 17, 93-101 Google Scholar
131. Rissin, D.M. et al. (2013) Multiplexed single molecule immunoassays. Lab on a Chip 13, 2902-2911 Google Scholar