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New drug-design strategy could help tackle mental disorders

A team of researchers at the University of California, San Diego, US, and the Institut Pasteur, France, have come up with a novel way to describe a time-dependent brain development based on coherent-gene-group (CGG) and transcription-factor (TF) hierarchy. The findings could lead to new drug designs for mental disorders such as autism-spectrum disorder and schizophrenia.

Image courtesy David Brooks.

"What we found was existence of the coherent gene groups that have interacting genes and which work as a multi-gene modules to regulate the brain development,” explains Igor Tsigelny, a research scientist with San Diego Supercomputer Center (SDSC), as well as UC San Diego Moores Cancer Center and the Department of Neurosciences.

These groups of genes act in concert to send signals at various levels of the hierarchy to other groups of genes, which control the general and more specific (depending on the level) events in brain structure development.

The researchers obtain microarray gene expression data from samples taken from three regions of the brains of rats on various days of development. They then use the Gordon supercomputer and SDSC's BiologicalNetworks server to conduct numerous levels of analysis.

“Microarray data are clusterized with SOMs [self-organizing maps] – which helps us not only group genes with similar behavior,but also see clearly the genes active for each day of development. Based on this information, zones are associated with significant developmental changes and brain disorders and genes are determined,” explains Valentina Kouznetsova, assistant project scientist at Moores Cancer Center.

Diagram showing the novel strategy of drug design based on hierarchical CGG–TF network analysis. The blue squares are schizophrenia-related; the red squares are autism-related CGGs and TFs. (Some CGGs and TFs are common for both disorders, while some are unique for each disorder.) Drugs can be administered at different hierarchical levels and delivered either to a set of possible targets or to the selected CGG. Image courtesy Igor Tsigelny.

After this initial processing, researchers conduct analyses of developmental stages and do quick comparisons between rat and human brain development. They also perform additional pathway analyses, as well as functional and hierarchical network analyses. “Using the microscope we are able to see the general picture as well as the finest details of gene–TF interactions,” notes Kouznetsova. By identifying these specific gene–TF interactions, the team is able to hone in on neurological disorders.

“We have proposed a novel, though still hypothetical, strategy of drug design based on this hierarchical network of TFs. This could pave the way for a new category of pharmacological agents, which could be used to block a pathway at a critical time during brain development,” notes Tsigelny. Ultimately, he envisions this as a potentially effective way to treat and even prevent mental disorders such as autism-spectrum disorder (ASD) and schizophrenia – and, on a broader scale, to change the paradigm of drug design. “We continue to work on hierarchical gene networks that control brain development. Currently we are studying the ASD-related gene networks, hoping to point out the TFs that we can affect on various stages of brain development. These interventions hopefully will be able to change the specified neuron development stages and normalize the brain development.”

A version of this story first appeared on the San Diego Supercomputer Center website.

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