Cellular mechanisms and physiological functions of cytochrome P450 derived eicosanoids in the model organism Caenorhabditis elegans

The aim of this project is to elucidate thus far largely unknown receptors and signalling pathways that mediate the biological effects of cytochrome P450 (CYP)-dependent eicosanoids by using the nematode Caenorhabditis elegans as model organism. CYP-eicosanoids comprise epoxy- and hydroxy-metabolites derived from long-chain polyunsaturated fatty acids, such as arachidonic acid (AA) and eicosapentaenoic acid (EPA). In mammals, these metabolites play important roles in the regulation of cardiovascular and renal function; however, their primary targets and detailed modes of action remained elusive.

Recent own studies showed that CYP-eicosanoids are similarly produced in C. elegans and contribute in this model organism to the regulation of food uptake and locomotive activity. Specifically, CYP-eicosanoids modulate pharyngeal pumping activities in response to food supply and satiation, presumably by functioning as second messengers of neurohormones like serotonin and octopamine. Moreover, CYP-eicosanoids mediate the rapid changes in worms locomotion speed upon anoxia/reoxygenation. Using established bioassays it was also shown that these behavioural responses are directly inducible by adding selected CYP-eicosanoids to cultured worms.

These findings offer now the unique opportunity to perform systematic RNA interference (RNAi) screens for identifying the genes involved in CYP-eicosanoid action. A further part is aimed at understanding the molecular interactions between neurohormones and CYP- eicosanoids in the regulation pharyngeal muscle activity and food uptake. Major open questions to be addressed concern the identity of the cell types, neurohormone receptors and phospholipases involved in eliciting the formation of CYP-eicosanoids as required for inducing the behavioural responses. Finally, studies are planned to prove the notion that the basic mechanisms of CYP-eicosanoid formation and action are evolutionary conserved. Here we search for human homologs of the CYP enzymes and signalling components identified in C. elegans and test their capacity to functionally rescue corresponding mutant strains.