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Defining the key requirements for sensing pain using mouse and fruit fly behavioural models and new gene ablation techniques


Chronic pain affects approximately ten percent of the population. Pain management is therefroe asignificant global concern. However, despite its prevalence, medicine has yet to offer an effectivetherapy for chronic pain.The goal of this proposal is to iden tify novel participants in the mammalian pain detection system, withthe long-term goal of targeting these novel participants to develop new painkillers. Our hypothesis isthat, due to its necessity for survival, the underlying mechanisms involved in sensing and reacting topain will be evolutionarily conserved. We propose to screen a complete Drosophila library to identifyall essential components involved in Drosophila pain detection. Taking this information, we will screenthe mouse genome for murine ortholog ues of these factors. We propose to create murine knockoutsdeficient in these orthologues, and then evaluate the ability of these mice to respond to pain. In micewith an impaired ability to respond to pain, we will use DNA microarrays to characterize the t issue-specific global gene expression patterns in various neuronal and non-neuronal tissues. Completion ofthis project should reveal all conserved mechanisms to sense pain.In addition to elucidating conserved mechanisms for detecting and sensing pain, our proposal attemptsto define a new paradigm for characterizing complex biological processes. We hypothesis that the basicmechanisms nature has selected to organize conserved complex biological processes will have beenafforded less evolutionary leeway. While specific players may have subtly different roles, the structureand conceptual organization of this complex process will be similar. Thus, we believe that invertebratemodels like Drosophila contain clear answers to how many complex mammalian systems areorga nized. We anticipate that the value of this approach will be established by revealing a commonconserved system of pain sensation. Once #

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Dr Bohrgasse 3-5