Final Report Summary - GATSNCE (Genetic Analysis of Temperature Sensation and Nociception in Caenorhabditis elegans) Pain is a major medical concern and there is an undeniable need to improve the therapeutic options in pain management. In this project, a simple model organism is used to identify and characterize new potential drug targets.Nociception is defined as the neural processes of encoding and processing pain-triggering stimuli, such as noxious temperature. The general goal of this research project is to shed new light on the molecular and neural basis of thermal nociception, by using the small nematode Caenorhabditis elegans. This model organism presents several advantages, including the availability of a complete nervous system wiring diagram, efficient genetic techniques, and a stereotyped avoidance behavior in response to noxious heat, providing a simple readout of thermal nociception. Recent work by the applicant has demonstrated the suitability of this model. New assays were developed to quantify heat avoidance behaviors and a pilot mutagenesis screen led to the identification of several genes, whose mutation impairs noxious heat avoidance. The specific goals pursued in the present project were:1) To characterize the interplay between the recently discovered “thermal avoidance” genes.We have performed a systematic epistasis analysis and discovered several genetic interactions among thermal avoidance genes. These findings will guide future studies to deepen our understanding of the signaling network into play.2) To identify more genes required for heat avoidanceThe screen for thermal avoidance genes was scaled up. Six new mutants were recovered and are currently being mapped with whole genome sequencing and high density SNPs. Once identified, these new mutants will provide novel entry points to further dissect the molecular control of nociception.3) To identify the neurons involvedBy using reporter genes and cell-specific genetic rescue in mutants, as well as neuron ablation, we have identified several neurons involved in thermal avoidance. By integrating these new data with information from the literature, such as the known wiring diagram of C. elegans nervous system, we can know propose a working model of the thermal avoidance circuit.4) To understand the logic of the thermal avoidance neural circuitSeveral optogenetic tools have been established. Current work aims at functionally testing our working model of the thermal avoidance circuit. Obtaining a deep understanding of the neural circuit controlling nociception and avoidance behaviors in C. elegans will provide a critical framework to speed up the characterization of newly identified nociception genes.Because nociception mechanisms appear to be largely conserved between worm and human, discovering and characterizing new nociception genes will provide novel insights on potential therapeutic targets for pain management.
