Background
Neuropathic organophosphorus (OPs) are used as chemical warfare agents (CWA), such as sarin [GB] and soman [GD], but also in industry (TOCP) and agriculture (chlorpyrifos). Exposition to neuropathic OPs is well-known to induce organophosphorus-induced delayed neuropathy (OPIDN), a neurodegenerative disorder characterized by a delayed onset of prolonged ataxia and upper motor neuron spasticity. Neuropathic OPs represent a significant military and terrorist threat for NATO countries, because not only civil population and troops can be exposed to CWA based in these groups of compounds, but also they can be exposed to neuropathic OPs used in the industry and agriculture, whether accidentally or if they are used in improvised explosive devices. Despite its significant risk for public health, no effective medical countermeasures for fighting against OPIDN are yet available. Increasing the current understanding of the pathophysiological processes resulting in OPIDN should allow the identification of new therapeutic targets and the development of specific medical countermeasures.
Objectives
The main objective of this projectis is to identify new therapeutics targets and potential treatments for organophosphorus-induced delayed neuropathy (OPIDN) by increasing the understanding of the pathological processes associated to this neurotoxic syndrome through an integrated approach using state of the art omic technologies and the powerful zebrafish model. To achieve this objective, four research objectives will be implemented:
1. To determine the molecular, subcellular, cellular and organismal in vivo response to neuropathic OPs in order to: (1) understand, and further characterize, the mechanism of toxicity of these neurotoxicants, and (2) identify new potencial therapeutic targets for OPIDN treatment.
2. To re-evaluate the role of the neuropathy target esterase (NTE) in the pathogenesis of OPIDN.
3. To identify new secondary targets of neuropathic OPs potentially involved in OPIDN development.
4. To perform an in vivo zebrafish directed screen of small molecules, selected as potencial modulator of the previously identified therapeutic targets, in order to identify antidotes able to protect the axons from the Wallerian degeneration induced by neuropathic OPs in OPIDN.
Specific workplan
1. Development of a zebrafish model of OPIDN.
2. Deciphering the patophysiological mechanisms associated to OPIDN development.
3. Analyzing the role of NTE inhibition on the development of OPIDN.
4. Involvement of unreported secondary targets in OPIDN
5. Directed screening of drugs protecting against OPIDN
Expected Outcomes
1. A characterization of the pathophysiological mechanisms conducting to OPIDN, and identification of new therapeutic targets, by the integration of data at different levels of organization, including molecular (transcriptome, proteome, lipidome and metabolome), subcellular (axonal transport), cellular (Wallerian degeneration), and organismal (impairment of motor behavior) levels.
2. A re-evaluation of the role played by NTE inhibition and aging on the development of OPIDN.
3. An identification of new secondary targets (enzymes/receptors) of neuropathic OPS potentially involved in OPIDN pathogenesis;
4. An identification of potential molecules protecting axons against the dyning-back axonopathy in OPIDN, by performing a directed screening of small molecules in zebrafish larvae exposed to neuropathic OPs.