RNA-Protein Interactions in Nociception

伤害感受中的 RNA-蛋白质相互作用

基本信息

批准号：
10446382
负责人：
Benjamin Harrison
金额：
$ 37.83万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446382
关键词：
Acute Adult Afferent Neurons Affinity Chromatography American Animal Model Attenuated Behavioral Binding Binding Proteins Biological Assay Capsaicin Carrageenan Cells Clinical Complex Computer Analysis Crush Injury Data Data Set Development Family Future Generations Genes Genetic Genetic Translation Health Histologic Hyperalgesia Hypersensitivity Inflammation Inflammation Process Inflammatory Injury Intervention Investigation Ion Channel Ion Channel Protein Knock-out Knockout Mice Knowledge Mass Spectrum Analysis Measures Mechanics Messenger RNA Minor Modeling Mus Neurons Neuropeptides Nociception Nociceptors Pain Pain Threshold Persistent pain Pharmacology Pre-Clinical Model Protein Biosynthesis Proteins Proteomics RNA RNA-Binding Proteins RNA-Protein Interaction Reflex action Regulon Reporting Ribosomes Role Sampling Sensory Spinal Ganglia Stimulus Syndrome Testing Therapeutic Therapeutic Intervention Transcript Translating Translations Treatment Efficacy Ursidae Family Viral Viral Vector Western Blotting animal pain base chronic pain chronic painful condition clinical pain cohort disability efficacy testing electrical property experimental study gain of function health care service utilization heat stimulus in silico in vivo inflammatory pain mechanical stimulus member mouse model nerve injury neuronal excitability neurotransmission new therapeutic target non-opioid analgesic novel novel therapeutics overexpression pain chronification pain inhibition pain model pain perception painful neuropathy patch clamp patient subsets pre-clinical preference response sciatic nerve injury sex single cell analysis single-cell RNA sequencing tissue injury tool trafficking transcriptome sequencing transmission process

项目摘要

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

抽象的持续性和慢性疼痛是通过感觉传入的可塑性制备的。最近的进步证明了这一点可塑性是通过促伤害性基因的从头翻译来启动和维持的。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率。所以，在感觉神经元中选择性调节亲人的mRNA翻译的蛋白质会发现为开发新颖的靶向疗法提供机会。 mRNA翻译受到调节 RNA结合蛋白（RBP）。我们对通过组织学证实的单细胞RNA-seq数据的分析评估显示，RBP的存在仅限于背根神经节（DRG）的亚群伤害性神经元。先前的研究表明，该RBP与mRNA的翻译结合并抑制与神经元兴奋性相关的转录本。我们的计算分析预测，这种伤害感受器受限的RBP将抑制一个离子通道，神经肽和其他“疼痛基因”的星座，从而抑制形成推定的抗伤害性调节。该提案将检验以下假设。总计通过结合并抑制促伤害感受器的翻译来抑制伤害性传播 mrnas。该建议将确定增强此RBP的功能是否是发展的可行策略使疼痛阈值正常化和反向慢性疼痛的干预措施。这样这些调查将展示了一种新型的抗伤害感受调节子，该调节量缩放疼痛感的阈值并验证使用发现负责过渡的因素的工具