3’ End Regulation in Nociceptor Plasticity

3â结束伤害感受器可塑性的调节

• 批准号: 9282915
• 负责人: Zachary Campbell
• 金额: $ 39.94万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282915
• 关键词: Afferent Neurons; Affinity Chromatography; American; Analgesics; Animals; Automobile Driving; Behavioral; Binding; Biochemistry; Bypass; Cellular biology; Chemicals; Complex; Development; Electrophysiology (science); Epidemic; Eukaryotic Initiation Factors; Evaluation; Event; Family; Gene Family; Gene Targeting; Generations; Genetic Transcription; Genetic Translation; Healthcare Systems; High-Throughput Nucleotide Sequencing; Homologous Gene; Human; Impairment; In Vitro; Incidence; Individual; Inflammatory; Injury; Integration Host Factors; Interleukin-6; Measurement; Mediating; Mediator of activation protein; Memory; Messenger RNA; Molecular; Motivation; Mus; Nerve Growth Factors; Neuronal Plasticity; Neurons; Nociception; Nociceptors; Oligonucleotides; Opioid; Pain; Pain management; Pharmacology; Platelet Factor 4; Play; Poly A; Poly(A) Tail; Poly(A)-Binding Proteins; Polyadenylation; Population; Production; Property; Protein Biosynthesis; Protein Inhibition; Protein Isoforms; Proteins; RNA Interference; RNA Sequences; RNA-Binding Proteins; Recruitment Activity; Regulation; Research; Ribosomal Proteins; Ribosomes; Role; Signal Transduction; Specificity; Spinal Ganglia; Structure; Technology; Testing; Transcript; Translating; Translation Initiation; Translations; Work; base; behavioral response; chronic pain; cytokine; design; experimental study; functional genomics; genome editing; improved; in vitro activity; in vivo; in vivo Model; inhibitor/antagonist; medical attention; mouse model; next generation sequencing; novel; protein function; response to injury; scaffold; translation factor; treatment strategy

Project Summary/Abstract Poorly managed pain creates an enormous burden on our healthcare system and produces tremendous human suffering. Following an injury, pain is caused by the production of inflammatory cytokines that induce changes in the excitability of nociceptor neurons. A better understanding of molecular mechanisms that facilitate nociceptor plasticity is vital for improved pain treatment. Post-transcriptional gene control has emerged as a dominant theme in pain induced plasticity. We focus on Poly(A) binding proteins (PABPs), a conserved family of 3’ end associated factors that regulate translation initiation and play prominent roles in development and memory. We will determine binding specificities for PABPs present in dorsal root ganglion (DRG) neurons using an unbiased next- generation sequencing approach. This information will be used to generate a novel class of chemically stabilized RNAs called specificity-derived competitive inhibitor oligonucleotides (SPOT-ONs). Unlike genome editing or RNA interference, SPOT-ONs are well tolerated and bypass the need for host-factors as they function as “decoys”. A major advantage of pharmacological inhibition as opposed to targeted gene disruption is the ability to simultaneously impair multiple homologues in a larger gene family. Our preliminary findings indicate that a bi- specific PABP SPOT-ON provides robust anti-hyperalgesic effects in vivo. Based on this finding, we hypothesize that PABPs are crucial mediators of plasticity in nociceptors. We describe preliminary development of SPOT- ONs which reduce protein synthesis in nociceptors and act specifically on poly(A)-mediated mRNA translation (Aim 1). We probe PABP mechanism of action through examination of localized translation and global identification of targets in nociceptors (Aim 2). Finally, we determine how PABP inhibition impacts nociceptor excitability and behavioral responses to injury (Aim 3).

项目概要/摘要 疼痛管理不善会给我们的医疗保健系统带来巨大的负担，并造成巨大的人力损失。 痛苦。受伤后，疼痛是由炎症细胞因子的产生引起的，炎症细胞因子会引起炎症细胞因子的变化。 伤害感受器神经元的兴奋性。更好地理解促进伤害感受器的分子机制 可塑性对于改善疼痛治疗至关重要。转录后基因控制已成为主导主题 疼痛引起的可塑性。我们专注于 Poly(A) 结合蛋白 (PABP)，这是一个 3' 端相关的保守家族 调节翻译起始并在发育和记忆中发挥重要作用的因素。我们将 使用无偏下一步确定背根神经节（DRG）神经元中存在的 PABP 的结合特异性 世代测序方法。该信息将用于生成一类新型化学稳定剂 RNA 称为特异性竞争性抑制剂寡核苷酸 (SPOT-ON)。与基因组编辑或 RNA 干扰，SPOT-ON 具有良好的耐受性，并且无需宿主因素，因为它们的功能如下： “诱饵”。与靶向基因破坏相比，药理学抑制的一个主要优点是能够 同时损害更大基因家族中的多个同源物。我们的初步研究结果表明，双 特定的 PABP SPOT-ON 在体内提供强大的抗痛觉过敏作用。基于这一发现，我们假设 PABP 是伤害感受器可塑性的重要介质。我们描述了 SPOT-的初步开发 ON 可减少伤害感受器中的蛋白质合成，并特异性作用于 Poly(A) 介导的 mRNA 翻译 （目标 1）。我们通过检查本地化翻译和全局翻译来探讨 PABP 的作用机制。 识别伤害感受器中的目标（目标 2）。最后，我们确定 PABP 抑制如何影响伤害感受器 兴奋性和对伤害的行为反应（目标 3）。