Molecular pathway analysis in human trabecular meshwork cells treated with dexamethasone
Creators: name: Liesenborghs, Ilona
name: Eijssen, Lars M.T.
name: Kutmon, Martina
name: Gorgels, Theo G.M.F.
name: Evelo, Chris T.
name: Beckers, Henny J.M.
name: Webers, Carroll A.B.
name: Schouten, Jan S.A.G.
Publisher: name: F1000Research
Year: 2016

description: Corticosteroids, used for the treatment of many different diseases in ophthalmology, cause an elevation of the eye pressure in 18-36% of patients. This may cause loss of visual field and eventually blindness (corticosteroid-induced glaucoma). The pathogenic mechanism is not completely understood, however, the trabecular meshwork seems to play an important role. To gain more insight into the pathogenic mechanisms, we performed pathway analysis of publicly available microarray datasets in which the gene expression of human trabecular meshwork cells treated with and without dexamethasone are compared.<br><br>A search for relevant microarray datasets was conducted in ArrayExpress and Gene Expression Omnibus (GEO). Four datasets were included (GSE16643 [1], GSE37474 [2], GSE65240 [3], and GSE6298 [4]). Quality control and pre-processing were performed with ArrayAnalysis.org and pathway overrepresentation analysis and visualization with PathVisio. Pathways with a Z-score &gt;1.96, a permuted p-value &lt;0.05, and ≥3 changed genes were considered significantly changed. Pathways that were significantly changed in at least three out of four studies were further investigated.<br><br>Pathway analysis of the above-described datasets showed respectively 21, 19, 39, and 21 significantly altered pathways. Five pathways were significantly affected in three out of four datasets: Complement Activation Pathway, Complement and Coagulation Cascade, Adipogenesis, Spinal Cord Injury, and the Differentiation Pathway. Some of these pathways are already known to be associated with glaucoma or corticosteroid induced effects. The five pathways were combined into a network that was used to evaluate possibilities for drug repurposing (drug-target interactions). We found 266 registered medicines that interact with the genes in the identified pathways.<br><br>In conclusion, by using systems biology we scrutinized, combined, and analysed the public gene expression data on corticosteroid-induced glaucoma. This approach is an efficient way to increase our insight into the molecular pathology and to discover new applications for drugs that are already registered for treatment of other diseases. <br><br>References: <br>[1] Nehme, A., E. K. Lobenhofer, W. D. Stamer and J. L. Edelman (2009). "Glucocorticoids with different chemical structures but similar glucocorticoid receptor potency regulate subsets of common and unique genes in human trabecular meshwork cells." BMC Med Genomics 2: 58.<br><br>[2] Markus H. Kuehn1, C. Y. K., Young H. Kwon (11/06/2012). "Dexamethasone induced gene expression changes in human perfusion organ cultured trabecular meshwork." Not published as an article.<br><br>[3] Matsuda, A., Y. Asada, K. Takakuwa, J. Sugita, A. Murakami and N. Ebihara (2015). "DNA Methylation Analysis of Human Trabecular Meshwork Cells During Dexamethasone Stimulation." Invest Ophthalmol Vis Sci 56(6): 3801-3809.<br><br>[4] Fan, B. J., D. Y. Wang, C. C. Tham, D. S. Lam and C. P. Pang (2008). "Gene expression profiles of human trabecular meshwork cells induced by triamcinolone and dexamethasone." Invest Ophthalmol Vis Sci 49(5): 1886-1897.