Project 463003

Millions of people will be affected by pain during their lifetime. These debilitating conditions can be triggered by injury, various diseases, or side effects of drugs. Nociception is a process in which sensory neurons detect painful stimuli and allow individuals to avoid potential tissue damage and death. Treating pain remains a costly and major challenge. A greater understanding of the underlying mechanisms of nociception is needed to develop new treatments. The genes and proteins involved in nociception and pain are conserved across organisms. In the present grant, we use the fruit fly, Drosophila melanogaster, to study cellular and molecular mechanisms underlying nociception. The process of nociception in the fruit fly is remarkably similar to how it works in mammals, including humans. Our preliminary data points to a key role for the calcium-binding protein Frequenin2 (Frq2), the Drosophila orthologue of Neuronal Calcium Sensor-1 (NCS-1), in nociception. In order to determine if Frq2/NCS-1 can be targeted for treating pain, several important questions must be addressed. In this grant, we will address whether this gene alters nociceptive sensitivity through changes in synaptic function or structure. Distinguishing between these effects is essential for developing treatments. We will also examine how drugs used in chemotherapy (paclitaxel), tissue injury, and Calpain regulate Frq2 expression and nociception. This will aid in understanding how drugs used in chemotherapy and tissue injury can affect nociception. Finally, we will determine how an interaction between Ric8a, a receptor-independent activator of G protein complexes, and Frq2 regulates nociception. This will provide insight into the mechanisms by which Frq2 regulates nociception. The findings from this grant will expand our knowledge of the underlying mechanism of nociception and identify new molecules that can potentially be targeted in treating pain.