Sreepradha Sridharan, BS (Advisor: Michael Galko, PhD)

Investigating the Role of Insulin-Like Signaling in Paclitaxel-Induced Nociceptive Hypersensitivity using Drosophila melanogaster

Paclitaxel (PTX), a chemotherapeutic that alters microtubule dynamics, is known to induce nociceptive hypersensitivity and sensory neuron damage in human patients and in Drosophila larvae. We used a modified feeding protocol to establish a genetically tractable Drosophila model of PTX-induced hypersensitivity. Larvae fed PTX exhibited hypersensitivity to thermal and mechanical stimuli. Thermal hypersensitivity was observed at low concentrations of PTX (even below 1 µM per ml of food), begins within 8 hours of PTX feeding, and did not completely resolve at the larval stage. Live imaging of peripheral thermal nociceptors showed that this hypersensitivity precedes observable neuronal damage. At low concentrations, PTX caused hyper-sprouting of tertiary dendritic spines in peripheral nociceptors. At high concentrations, it caused dendritic degradation. We used this model of PTX-induced hypersensitivity to explore its molecular/genetic basis. Of particular interest was insulin-like signaling (ILS) which regulates the persistence of damage-induced hypersensitivity. RNAi targeting the insulin receptor (InR) in nociceptors increased PTX-induced hypersensitivity. However, insulin-like peptide 4 (ILP4), was only required for PTX-induced thermal hypersensitivity at 10 µM. In summary, our model of PTX-induced hypersensitivity revealed a disconnect between hypersensitivity and neuronal morphology and a genetic separation of ILP4 and InR in PTX-induced hypersensitivity.

Advisory Committee:

• Michael Galko, PhD, Chair
• Mark Bedford, PhD
• George Eisenhoffer, PhD
• Honami Naora, PhD
• Sheng Zhang, PhD