Network analysis of human glaucomatous optic nerve head astrocytes
- Equal contributors
1 Vavilov Institute of General Genetics, Russian Academy of Sciences, 3 Gubkina Str, Moscow, Russia
2 GeneGo Inc, 500 Renaissance Drive, Suite 106, St. Joseph, MI, 49085, USA
3 Current address: Bascom Palmer Eye Institute Department of Ophthalmology, University of Miami Miller School of Medicine; 1638 NW 10th Avenue, Miami, FL 33136, USA
4 Department of Molecular Biology and Biochemistry, University of Miami Miller School of Medicine, 1638 NW 10th Avenue, Miami, FL 33136, USA
5 Department of Ophthalmology and Visual Sciences Washington University School of Medicine 660 South Euclid Ave, St Louis, MO 63110, USA
6 Department of Ophthalmology, Feinberg School of Medicine, Northwestern University Chicago, IL 60611, USA
7 Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, 1638 NW 10th Avenue, Miami, FL 33136, USA
BMC Medical Genomics 2009, 2:24 doi:10.1186/1755-8794-2-24Published: 9 May 2009
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.
To 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).
Our 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.
Our 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.