Development of Neural Protectants Against Organophosphorus Compound Toxicity

We propose to develop a novel methodology to systematically develop therapeutic compounds for treatment of organophosphate (OP) induced neurotoxicity. A core hypothesis is that combined temporal measurement and computational analysis of cellular processes is needed to understand neurotoxicity and discover novel therapeutics/protectants. We propose a combination of experiment and computation whose goal is to elucidate a detailed mechanistic description of OP neurotoxicity including signalingpathways, metabolic effects and biochemical markers. Starting from current knowledge, we will construct a map of neural signaling/activity pathways and identify reporters of modulation by OP compounds. Using a modified microphysiometer, the dynamic metabolic and signaling changes in neurotypical PC12 cell will be probed. Network analysis tools will be used to analyze the experimental data, in order to validate/modify proposed pathways. Sensitivity analyses will be performed to identify control points for efficaceous intervention. In Phase II, with the aid of expanded measurements, intervention points and candidate therapeutic compounds will be identified. A multi-disciplinary partnership with expertise in (a) dynamic measurements of cellular toxicology/metabolism and (b) in-silico modeling of cellular signaling/metabolism and (c) neurotoxicology has been assembled. The research will be leveraged on ongoing efforts related to analysis of toxin exposure effects both at Vanderbilt and CFDRC.