Network analysis of human glaucomatous optic nerve head astrocytes.
BACKGROUND
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Nikolskaya
Tatiana
T
Vavilov Institute of General Genetics, Russian Academy of Sciences, 3 Gubkina Str, Moscow, Russia.
Nikolsky
Yuri
Y
Serebryiskaya
Tatiana
T
Zvereva
Svetlana
S
Sviridov
Eugene
E
Dezso
Zoltan
Z
Rahkmatulin
Eugene
E
Brennan
Richard J
RJ
Yankovsky
Nick
N
Bhattacharya
Sanjoy K
SK
Agapova
Olga
O
Hernandez
M Rosario
MR
Shestopalov
Valery I
VI