Abstract
BackgroundAstrocyte activation is a characteristic response to injury in the central nervous system, and can be either neurotoxic or neuroprotective, while the regulation of both roles remains elusive.MethodsTo decipher the regulatory elements controlling astrocyte-mediated neurotoxicity in glaucoma, we conducted a systems-level functional analysis of gene expression, proteomic and genetic data associated with reactive optic nerve head astrocytes (ONHAs).ResultsOur reconstruction of the molecular interactions affected by glaucoma revealed multi-domain biological networks controlling activation of ONHAs at the level of intercellular stimuli, intracellular signaling and core effectors. The analysis revealed that synergistic action of the transcription factors AP-1, vitamin D receptor and Nuclear Factor-kappaB in cross-activation of multiple pathways, including inflammatory cytokines, complement, clusterin, ephrins, and multiple metabolic pathways. We found that the products of over two thirds of genes linked to glaucoma by genetic analysis can be functionally interconnected into one epistatic network via experimentally-validated interactions. Finally, we built and analyzed an integrative disease pathology network from a combined set of genes revealed in genetic studies, genes differentially expressed in glaucoma and closely connected genes/proteins in the interactome.ConclusionOur results suggest several key biological network modules that are involved in regulating neurotoxicity of reactive astrocytes in glaucoma, and comprise potential targets for cell-based therapy.
Highlights
Astrocyte activation is a characteristic response to injury in the central nervous system, and can be either neurotoxic or neuroprotective, while the regulation of both roles remains elusive
The gene expression data analysis performed here revealed the changes in the disease-imprinted optic nerve head astrocytes (ONHAs), an experimental strategy that is often implemented by other investigators working with human diseases [24,25]
We combined the data from donor Groups #1 and #2, which contained tissues from four glaucomatous and three or four normal eyes each into a non-redundant data set comprised of 461 up-regulated genes and 301 down-regulated genes, and analyzed it along with individual data sets from each experimental series separately
Summary
Astrocyte activation is a characteristic response to injury in the central nervous system, and can be either neurotoxic or neuroprotective, while the regulation of both roles remains elusive. Recent progress in systems biology has allowed a quantification, cross-comparison and functional interpretation of heterogeneous datasets within the framework of human biological pathways, networks and processes, which are assembled from a knowledgebase of functional biological interactions [10,11] This systems level approach requires an understanding of connectivity between the genes and proteins affected in a given disease. The biological networks are scale-free but converge in regulatory nodes and modules, such as major transcription factors and receptors [13,14] Identification of such key topological elements [15,16] on the networks derived from disease-related data may reveal potential therapeutic targets. This approach is powerful for diseases of complex etiology, such as glaucoma
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