Monday, May 6, 2024
5/6/2024
Project Summary: Targeted degradation of NaV1.8 as a therapeutic strategy for pain. Chronic pain is a massive global health burden, and therapeutic options for pain are limited and have a spectrum of adverse effects. Alternative treatments for pain that are specific, effective, and non-addictive are an urgent need. NaV1.8 channels are critical determinants of nociceptor excitability—they contribute to most of the current underlying the rising phase of action potentials and have been implicated in human pain conditions and in animal models of pain. Gain-of-function mutations in NaV1.8 result in painful neuropathies in humans, and a loss-of- function in NaV1.8 dulls pain sensitivity in animal models. This genetic dichotomy suggests that reducing sodium influx through NaV1.8 channels can provide analgesia without CNS side-effects or addictive potential. To date, the principal strategy for targeting these channels has been to directly inhibit sodium conductance through the channel. While promising, agents with this mechanism of action have not yet been deployed in the clinic. An innovative approach may be to reduce the number of channels present at the neuronal surface by selective degradation. I have generated a bifunctional protein (named UbiquiNaV) composed of a NaV1.8 selective binding sequence and the catalytic domain of the NEDD4 ubiquitin ligase. This engineered protein should bind specifically to NaV1.8 and subsequently ubiquitinate the channel, targeting it for degradation. My preliminary data shows that expression of UbiquiNaV in rat DRG neurons reduces NaV1.8 current. This proposal will test the hypothesis that this bifunctional molecule will reduce nociceptor excitability via selective degradation of NaV1.8 channels. In Aim 1, I will investigate the specificity of UbiquiNaV for NaV1.8 and demonstrate how UbiquiNaV expression impacts rat nociceptor excitability. Aim 2 will use a live-cell imaging assay developed in our lab coupled with an inducible activation mechanism to examine the temporal and spatial regulation of NaV1.8 channels in DRG neurons by UbiquiNaV. Together, my work will a) delineate the mechanism of action of this newly engineered bifunctional molecule, and b) reveal the selectivity of UbiquiNaV for NaV1.8. In doing so, this work will demonstrate the viability of targeted degradation of NaV1.8 as an analgesic strategy.
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