RNA-Protein Interactions in Nociception

摘要 感觉传入的可塑性促进了持续性和慢性疼痛的发生。最近的进展证明了这一点。 可塑性是由伤害性基因的从头翻译启动和维持的。在动物模型中， 蛋白质翻译的药理和遗传扰动已显示出治疗效果。因此， 发现选择性调节感觉神经元伤害感受性基因翻译的蛋白质将 为新的靶向疗法的发展提供机会。信使核糖核酸的翻译受 RNA结合蛋白(RBPs)。我们对单细胞RNA-Seq数据的分析得到了组织学证实 评估揭示了仅限于背根神经节(DRG)亚群的RBP的存在 伤害性神经元。以前的研究表明，这种RBP结合并抑制mRNA的翻译 与神经元兴奋性相关的转录本。我们的计算分析预测这种伤害性感受器- 限制性RBP可以抑制一系列离子通道、神经肽和其他“疼痛基因”，从而 形成一个假定的反伤害感受调节子。这项提议将检验这样一种假设，即识别出的RBP 通过结合和抑制前伤害性感受器的翻译来强直地抑制伤害性传递 MRNAs。这项建议将决定加强这一RBP的功能是否是一个可行的发展战略 使疼痛阈值正常化并逆转慢性疼痛的干预措施。在这样做时，这些调查将 展示一种新的抗伤害性调节因子，它可以提高疼痛感知的阈值，并验证 用于发现导致过渡的因素的工具

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