Thursday, November 21, 2024
11/21/2024
ABSTRACT Persistent and chronic pain are facilitated by plasticity of sensory afferents. Recent advances demonstrate this plasticity is initiated and maintained by de novo translation of pro-nociceptive genes. In animal models, pharmacological and genetic perturbations of protein translation have shown therapeutic efficacy. Therefore, discovery of proteins that selectively regulate pro-nociceptive mRNA translation in sensory neurons would provide opportunities for the development of novel targeted therapeutics. mRNA translation is regulated by RNA-Binding proteins (RBPs). Our analyses of single cell RNA-Seq data confirmed by histological assessments revealed the presence of a RBP restricted to subpopulations of dorsal root ganglion (DRG) nociceptive neurons. Previous studies indicate that this RBP binds to and inhibits translation of mRNA transcripts associated with neuronal excitability. Our computational analyses predicted that this nociceptor- restricted RBP would suppress a constellation of ion channels, neuropeptides and other “pain genes”, thereby forming a putative anti-nociceptive regulon. This proposal will test the hypothesis that this identified RBP tonically suppresses nociceptive transmission by binding to and inhibiting translation of pro-nociceptive mRNAs. This proposal will determine if enhancing the function of this RBP is a viable strategy to develop interventions that normalize pain thresholds and reverse chronic pain. In doing so these investigations will demonstrate a novel anti-nociceptive regulon that scales the threshold for pain perception and validate use of a tool to discover factors responsible for the transition
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