In silico analysis of the molecular machinery underlying aqueous humor production: potential implications for glaucoma (original) (raw)
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Proteomic Alterations in Aqueous Humor From Patients With Primary Open Angle Glaucoma
Investigative ophthalmology & visual science, 2018
Primary open angle glaucoma (POAG) is the most prevalent form of glaucoma, accounting for approximately 90% of all cases. The aqueous humor (AH), a biological fluid in the anterior and posterior chambers of the eye, is involved in a multitude of functions including the maintenance of IOP and ocular homeostasis. This fluid is very close to the pathologic site and is also known to have a significant role in glaucoma pathogenesis. The purpose of this study was to identify proteomic alterations in AH from patients with POAG. AH samples were extracted from 47 patients undergoing cataract surgery (controls: n = 32; POAG: n = 15). Proteomic analysis of the digested samples was accomplished by liquid-chromatography-mass spectrometry. The identified proteins were evaluated using a variety of statistical and bioinformatics methods. A total of 33 proteins were significantly altered in POAG subjects compared with the controls. The most abundant proteins in POAG subjects are IGKC (13.56-fold), I...
Current Ophthalmology Reports, 2015
Primary open angle glaucoma (POAG) is the second leading cause of blindness in the world's rapidly aging population. POAG is characterized by progressive degeneration of neural structures in the posterior segment, often associated with a concomitant elevation of intraocular pressure. Changes in IOP are believed to be caused by a disruption in the normal outflow of aqueous humor. This article reviews recent research associated with normal and POAG aqueous humor outflow. Novel findings elucidating biochemical and pathological changes in the ocular tissues affected in POAG are presented. Stem cell research, identification of lymphatic markers, and increased use of mouse models give researchers exciting new tools to understand aqueous humor outflow, changes associated with POAG and identify underlying causes of the disease.
Differentiation of soluble aqueous humor metabolites in primary open angle glaucoma and controls
Experimental Eye Research, 2020
We report an analysis of the aqueous humor (AH) metabolome of primary open angle glaucoma (POAG) in comparison to normal controls. The AH samples were obtained from human donors [control (n=35), POAG (n=23)]. The AH samples were subjected to one-dimensional 1 H nuclear magnetic resonance (NMR) analyses on a Bruker Avance 600 MHz instrument with a 1.7mM NMR probe. The same samples were then subjected to isotopic ratio outlier analysis (IROA) using a Q Exactive orbitrap mass spectrometer after chromatography on an Accela 600 HPLC. Clusterfinder Build 3.1.10 was used for identification and quantification based on long-term metabolite matrix standards. In total, 278 metabolites were identified in control samples and 273 in POAG AH. The metabolites identified were fed into previously reported proteome and genome information and the OmicsNet interaction network generator to construct a protein-metabolite interactions network with an embedded protein-protein network. Significant differences in metabolite composition in POAG compared to controls were identified indicating potential protein/gene pathways associated with these metabolites. These results will expand our previous understanding of the impeded AH metabolite composition, provide new insight into the regulation of AH outflow, and likely aid in future AH and trabecular meshwork multi-omics network analyses.
Proteome Alterations in Primary Open Angle Glaucoma Aqueous Humor
Journal of Proteome Research, 2010
As the only nourishment and scavenging source for most of the anterior and posterior chamber tissues in the eye, the aqueous humor represents one of the target for glaucoma. The aim of this study is to investigate the yet unexplored relationship between aqueous humor protein content and open-angle glaucoma (POAG) pathogenesis. Aqueous humor was collected from 10 POAG patients (cases) and 14 senile cataract patients (controls), matched for age and gender, undergoing surgery for trabeculectomy and cataract, respectively. Protein samples were cyanine-labeled and hybridized with antibody microarrays. Microarray signals were revealed by laser scanner, quantified, and compared by statistical analyses. Total protein amounts were not significantly different in patients versus controls. Conversely, a proteome cluster significantly modified in patients as compared to controls was identified as highly predictive for disease status. Selected proteins underwent dramatic variation, which was correlated to pathogenetic events characterizing POAG, including oxidative damage, mitochondrial damage, neural degeneration, and apoptosis. The results obtained indicate that proteomic analysis of aqueous humor is a new tool for POAG diagnosis in the case of otherwise uncertain disease recognition. Furthermore, this study allows a better understanding of mechanisms involved in the pathogenesis of POAG, the main cause of irreversible blindness worldwide.
Differential expression of proteome in aqueous humor in patients with and without glaucoma
Archivos De La Sociedad Española De Oftalmología (english Edition), 2018
Objective: To determine quantitative and qualitative differences of aqueous humor proteome in patients with and without glaucoma. Method: Observational, descriptive and cross-sectional study of 12 patients (8 men; 4 women) with and without glaucoma. There are 3 groups of minority proteins with serum equimolar contribution of each of the patients. Specimens were obtained during cataract surgery from patients without glaucoma (performed with retrobulbar anesthesia [cataract retrobulbar patient-CRP; n = 4] or topical [cataract topical patient-CTP; n = 4]), or from patients with glaucoma (performed with retrobulbar anesthesia [glaucoma retrobulbar patient-GRP; n = 4]). The humor proteome samples were frozen at −80 • C until processing by trypsin digestion to obtain tryptic peptides, and then performing liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) to obtain the proteome and its differential expression between groups. Statistical analysis was performed using the SPSS v.17 program. Results: The study included 12 patients, aged (mean ± standard deviation) 74.50 ± 9.53 years. Concentrations obtained: 0.48 ± 0.25 g/l for CRP, 0.28 ± 0.04 g/l for CTP, and 0.35 ± 0.16 g/l for GRP. A total of 309 proteins were identified, of which 205, 210, and 182 were in CRP, CTP, and GRP, respectively. A total of 114 proteins were common to all three groups, 50 were exclusive to CRP, 58 to CTP, and 27 to GRP. Conclusions: In this pilot study, a quantitative difference was found in the protein expression of humor among patients with glaucoma, there being 27 proteins unique to patients with glaucomatous disease.
Expression Profiling of Human Schlemm's Canal Endothelial Cells From Eyes With and Without Glaucoma
Investigative ophthalmology & visual science, 2015
Ocular hypertension is a major risk factor for glaucoma and the inner wall of Schlemm's canal (SC) endothelia participates in the regulation of aqueous humor outflow resistance. This study aimed to identify differentially expressed genes in primary cultures of SC cells from glaucoma patients. This study examined SC samples from three glaucoma cases and four controls. Schlemm's canal cells were isolated from eight different postmortem human eyes. Total RNA was extracted, labeled, and hybridized to Illumina HumanWG-6 BeadChips containing probes for approximately 47,000 human transcripts. After extracting the data using Illumina GenomeStudio software, the data were normalized and analyzed using the R package limma in Bioconductor. Using Protein ANalysis THrough Evolutionary Relationships (PANTHER) software, gene ontology analysis of highly expressed genes was executed in controls and glaucoma groups separately. Pathway analysis was performed with differentially expressed genes ...
Progress in retinal and eye research, 2007
The discovery in the human ocular ciliary body of glaucoma-associated genes (i.e., MYOC, CYP1B1), neuroendocrine processing enzymes, neuroendocrine peptides, steroid-converting enzymes, glutamate transporters, glutamate-metabolizing enzymes, and antiangiogenic factors requires a reevaluation of its function on aqueous humor secretion, intraocular pressure and its role in glaucoma. The ciliary body should be considered as a multifunctional and interactive tissue. The intrinsic hypotensive and/or hypertensive biological activities of many of the endocrine peptides released by the ciliary epithelium are best explained within the context of a neuroendocrine system, linking the inflow and the outflow of aqueous humor. This interpretation is consistent with physiological and genetic studies indicating that changes altering the inflow affects intraocular pressure. In the proposed endocrine system, regulatory peptides secreted by the ciliary epithelium may subserve multiple functions in the following: inflow and outflow pathways of aqueous humor, ciliary blood flow, the immune privilege status of the anterior segment and the diurnal circadian rhythms of aqueous humor secretion and intraocular pressure. These previously unsuspected and challenging functions of the ciliary epithelium should be considered when assessing the multifactorial events which lead to the pathophysiology of glaucoma affecting the outflow pathways of aqueous humor. This review highlights published, and ongoing studies on authors' labs supporting neuroendocrine, steroidogenic and glutamatergic features of the ciliary epithelium and the endocrine communication between the inflow and outflow pathways of aqueous humor. We also discuss how glaucoma-associated genes expressed in the ciliary body and their mutant proteins could influence intraocular pressure, contributing to the development of glaucoma. r
Acta Ophthalmologica, 2019
PurposePerforming bioinformatics analyses using trabecular meshwork (TM) gene expression data in order to further elucidate the molecular pathogenesis of primary open‐angle glaucoma (POAG), and to identify candidate target genes.MethodsA systematic search in Gene Expression Omnibus and ArrayExpress was conducted, and quality control and preprocessing of the data was performed with ArrayAnalysis.org. Molecular pathway overrepresentation analysis was performed with PathVisio using pathway content from three pathway databases: WikiPathways, KEGG and Reactome. In addition, Gene Ontology (GO) analysis was performed on the gene expression data. The significantly changed pathways were clustered into functional categories which were combined into a network of connected genes.ResultsNinety‐two significantly changed pathways were clustered into five functional categories: extracellular matrix (ECM), inflammation, complement activation, senescence and Rho GTPase signalling. ECM included pathwa...