Genome-based Drug Repositioning as a Viable Option for the Identification of New Epilepsy Treatments
Conference Year
January 2019
Abstract
Temporal Lobe Epilepsy (TLE) is a chronic disorder characterized by recurrent seizures and hippocampal sclerosis and is often refractory to treatment. Our goal was to combine bioinformatic and drug repositioning tools to illustrate the gene expression changes seen in a rat pilocarpine epilepsy model, find hub genes mediating epileptogenesis, and identify drugs that will counteract this process to prevent TLE. Differential gene expression profiles were clustered into modules using weighted gene co-expression analysis of a rat pilocarpine microarray dataset. Fourteen modules were found to be significant after one-way ANOVA with Bonferroni correction; and up- or downregulated signatures within a module for time points after status epilepticus and after onset of spontaneous seizures were determined using Tukey HSD test. Gene Ontology terms were used to functionally characterize modules: terms mapped to upregulated modules at time points immediately after pilocarpine-induced status epilepticus (Day 3) reflected inflammatory and immune responses and terms mapped to downregulated modules reflected perturbed neuronal signaling and development. Genes within a module were ranked according to how closely they were associated with the module eigengene, the first principal component representing the expression pattern of that module. The top genes in the up- and downregulated modules after Day 3 were inputted into Connectivity Map as up and down query tags in order to find perturbagens that interact with the query genes. Vorinostat and trichostatin A, two histone deacetylase inhibitors, were identified as highly anticorrelated with the query genes. Others have also identified vorinostat as a potential drug to repurpose in the context of epilepsy, thereby adding support to this methodology as well as vorinostat’s candidacy as a therapeutic.
Primary Faculty Mentor Name
Matt Mahoney
Status
Graduate
Student College
Graduate College
Program/Major
Neuroscience
Primary Research Category
Biological Sciences
Genome-based Drug Repositioning as a Viable Option for the Identification of New Epilepsy Treatments
Temporal Lobe Epilepsy (TLE) is a chronic disorder characterized by recurrent seizures and hippocampal sclerosis and is often refractory to treatment. Our goal was to combine bioinformatic and drug repositioning tools to illustrate the gene expression changes seen in a rat pilocarpine epilepsy model, find hub genes mediating epileptogenesis, and identify drugs that will counteract this process to prevent TLE. Differential gene expression profiles were clustered into modules using weighted gene co-expression analysis of a rat pilocarpine microarray dataset. Fourteen modules were found to be significant after one-way ANOVA with Bonferroni correction; and up- or downregulated signatures within a module for time points after status epilepticus and after onset of spontaneous seizures were determined using Tukey HSD test. Gene Ontology terms were used to functionally characterize modules: terms mapped to upregulated modules at time points immediately after pilocarpine-induced status epilepticus (Day 3) reflected inflammatory and immune responses and terms mapped to downregulated modules reflected perturbed neuronal signaling and development. Genes within a module were ranked according to how closely they were associated with the module eigengene, the first principal component representing the expression pattern of that module. The top genes in the up- and downregulated modules after Day 3 were inputted into Connectivity Map as up and down query tags in order to find perturbagens that interact with the query genes. Vorinostat and trichostatin A, two histone deacetylase inhibitors, were identified as highly anticorrelated with the query genes. Others have also identified vorinostat as a potential drug to repurpose in the context of epilepsy, thereby adding support to this methodology as well as vorinostat’s candidacy as a therapeutic.