Genetic control of nociceptor anatomical plasticity in the adult peripheral nervous system

成人周围神经系统伤害感受器解剖可塑性的遗传控制

• 批准号: 10176521
• 负责人: Benjamin Harrison
• 金额: $ 24.85万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176521
• 关键词: 3' Untranslated Regions; Address; Adult; Afferent Neurons; Anatomy; Area; Axon; Behavior assessment; Binding; Binding Proteins; Chronic; Clinical; Crush Injury; Cutaneous; Development; Differentiation and Growth; Dorsal; Fiber; Foxes; Ganglia; Genetic; Genetic Transcription; Genomics; Glutamine; Goals; Growth; Histologic; Homeostasis; Homologous Gene; Human; Injury; Knock-out; Knockout Mice; Lead; Modeling; Molecular; Morphogenesis; Mus; Natural regeneration; Nerve; Nerve Crush; Neurons; Nociception; Nociceptors; Pain; Pathologic; Pattern; Pelvic Pain; Peripheral; Peripheral Nervous System; Persistent pain; Pharmacologic Substance; Phenotype; Population; Precipitation; Process; Proline; Protein Isoforms; Protein Splicing; RNA; RNA Splicing; RNA-Binding Proteins; Recovery; Recovery of Function; Regulation; Reporter; Role; Sensory; Sensory Ganglia; Spinal Ganglia; Syndrome; Technology; Testing; Therapeutic; Tissues; Tracer; Transcript; Untranslated Regions; Work; axon growth; axon regeneration; axonal sprouting; behavioral response; bioinformatics tool; chronic pain; computerized tools; density; dermatome; diabetic patient; differential expression; experience; experimental study; falls; injured; innovation; laser capture microdissection; nerve injury; nerve supply; novel; painful neuropathy; programs; response; response to injury; sciatic nerve; therapeutic target; therapy design; therapy development; tissue injury; transcriptome sequencing; transcriptomics

Many human clinical conditions are associated with misrelated loss or growth of sensory axons in peripheral tissue. These conditions are often associated with chronic/persistent pain. Examples are many and diverse, ranging from the painful progressive innervation loss experienced by many diabetic patients, to hyperdense nociceptor innervation associated with pelvic pain, to neuropathic pain following tissue and nerve injuries. In spite of a clear association between intractable chronic pain, nociceptor sensitization and innervation density, there are currently no pharmaceutical treatments designed to modify the extent of sensory fibers – either to promote re-growth or to control overgrowth. It is hoped that by elucidating the molecular control of axon growth processes, we may be able develop therapies to re-establish innervation homeostasis required to alleviate pain. Sensory neurons have a limited but significant capacity to grow following peripheral injury. We determined that nociceptors grow by 2 distinct modes: 1) regeneration after direct injury to their axons - termed injury-regeneration (IR) and 2) growth of near- by uninjured nociceptors, which extend collaterals to re-establish lost innervation - termed uninjured-sprouting (US). Using transcriptomic technology, we discovered striking differences in 3’ Untranslated Region (3’-UTR) transcript isoforms between these 2 modes of growth. These distinct patterns of 3’-UTR expression are predicted to promote physical interaction with different RNA-binding proteins (RBPs). We theorize that US and IR are distinct modes of axon outgrowth differentiated by the interplay between contrasting groups of 3’UTR isoforms and the different RBPs that regulate these transcripts. Our long term goal is to develop therapeutics that target growth mode-specific RBPs to modify distinct forms of nociceptor morphogenesis that are dysregulated under pathological conditions that lead to chronic pain. To work towards this goal, in this proposal we will determine the role of RNA-binding proteins (RBPs) in 3’UTR isoform regulation during distinct modes of axon outgrowth: Injury-Regeneration (IR) and Uninjured-Sprouting (US). Studies will fall into 3 aims. In aim 1 we will determine the role of RBPs during US and in aim 2 we will determine the role of RBPs during IR. The third aim will examine the role of 3’UTR isoform expression in neuropathic pain after sciatic nerve crush injury. This proposal tests a highly novel mechanism for the regulation of nociceptive fiber growth. The proposed experiments will elucidate molecular mechanisms underlying distinct modes of axonal outgrowth (IR and US) that may contribute to development of neuropathic pain. !

许多人类临床病症与外周感觉轴突的错误丧失或生长有关。 组织。这些病症通常与慢性/持续性疼痛有关。例子很多而且多种多样， 从许多糖尿病患者经历的痛苦的进行性神经支配丧失到高密度 与骨盆疼痛相关的伤害感受器神经支配，以及组织和神经损伤后的神经性疼痛。在 尽管顽固性慢性疼痛、伤害感受器敏化和神经支配密度之间存在明显的关联， 目前还没有药物治疗可以改变感觉纤维的范围——或者 促进再生长或控制过度生长。 希望通过阐明轴突生长过程的分子控制，我们也许能够开发出 重新建立减轻疼痛所需的神经支配稳态的疗法。感觉神经元的功能有限 但在周围损伤后具有显着的生长能力。我们确定伤害感受器的生长速度有两种不同 模式：1）轴突直接损伤后的再生 - 称为损伤再生（IR）和 2）近轴突的生长 通过未受伤的伤害感受器，延伸侧支以重新建立失去的神经支配 - 称为未受伤的发芽 （我们）。使用转录组技术，我们发现 3' 非翻译区 (3'-UTR) 存在显着差异 这两种生长模式之间的转录亚型。 3'-UTR 表达的这些不同模式是 预计可促进与不同 RNA 结合蛋白 (RBP) 的物理相互作用。我们的理论是美国和 IR 是轴突生长的不同模式，通过 3'UTR 对比组之间的相互作用来区分 同种型和调节这些转录本的不同 RBP。 我们的长期目标是开发针对生长模式特异性 RBP 的疗法，以改变不同形式的 伤害感受器形态发生在导致慢性疼痛的病理条件下失调。到 为了实现这一目标，在本提案中，我们将确定 RNA 结合蛋白 (RBP) 在 3’UTR 中的作用 轴突生长的不同模式期间的亚型调节：损伤再生（IR）和未损伤发芽 （我们）。研究将分为三个目标。在目标 1 中，我们将确定 RBP 在美国期间的作用，在目标 2 中，我们将 确定 RBP 在 IR 过程中的作用。第三个目标是研究 3’UTR 同工型表达在 坐骨神经挤压损伤后的神经性疼痛。该提案测试了一种高度新颖的机制 调节伤害性纤维生长。拟议的实验将阐明分子机制 轴突生长的不同模式（IR和US）可能有助于神经病的发展 疼痛。 ！