Profiling Translation in Nociceptor Plasticity

PROJECT SUMMARY/ABSTRACT Chronic pain is pervasive and devastating. It diminishes quality of life for 20% of adults. An integral feature of persistent pain is increased excitability in nociceptive sensory neurons. The molecular mechanisms that orchestrate plasticity in nociceptors are unclear. The integrated stress response (ISR) is a master regulator of neuronal function. Activation of the ISR triggers global suppression of translation and initiates pain through direct effects on sensory neurons. Four upstream kinases trigger the ISR through phosphorylation of the regulatory subunit of eukaryotic initiation factor 2. We recently discovered that one of these kinases, general control nonderepressible 2 (GCN2) is uniquely critical. Virtually nothing is known about the function of GCN2 in pain signaling. We will focus on resolving this problem in the following two aims: Aim 1 – Define the role of GCN2 in pain. Aim 2 – Examine the landscape of translation in the DRG during neuropathic pain. This work is broadly significant for the following reasons. The targets of translational regulation in neuropathic pain are unclear. We apply a transformative genomics tool that reveals molecular underpinnings of translational regulation with astonishing molecular clarity. Parallel experiments will identify relevant factors using a novel CRISPR/Cas9 in vivo perturbation strategy. The master regulatory factors that govern translational regulation in neuropathic pain are unclear. Our preliminary data at the molecular, cellular, and organismal levels provide strong evidence that GCN2 is critical.