A Systems Biology Approach to Enable Safe Administration of Mefloquine

The objective of this effort is to apply a systems-biology-centered methodology for the identification of subcellular mechanisms of mefloquine neurotoxicity, with the goal of developing a genetic profile to identify individuals predisposed to mefloquine neurotoxicity. The core hypothesis is that elucidating subcellular mechanisms of mefloquine neurotoxicity requires the combination of cellular level measurements and computational analysis of validated intracellular pathway models. Microarray analysis will determine the dose/response of cells exposed to mefloquine. Gene expression data combined with scientific literature, and expert guidance will be used to construct a pathway model of mefloquine neurotoxicity. The pathway model will be validated/modified using novel computational methods and gene silencing experiments. Sensitivity analysis will be performed to identify the critical pathways involved in mefloquine neurotoxicity. In Phase II, the critical pathways will be used to develop a genetic profile, including specific single nucleotide polymorphisms, capable of predicting mefloquine-induced neurotoxicity, ultimately enabling the development and commercialization of a test kit to identify individuals susceptible to mefloquine neurotoxicity. A multi-disciplinary partnership with expertise in (a) experimental measurements of cellular toxicology and (b) in silico analysis of pathway models has been assembled. This project will be leveraged off of multiple, ongoing research efforts aimed at constructing predictive intracellular pathway models to develop understanding of neurotoxic response to metal ions and organophosphorous compounds.