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

许多人类临床病症与外周神经系统中感觉轴突的错误丢失或生长有关。 组织.这些病症通常与慢性/持续性疼痛有关。例子有很多，而且多种多样， 范围从许多糖尿病患者经历的疼痛的进行性神经支配丧失，到高密度的 与骨盆疼痛相关的伤害性感受器神经支配，到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， 目前还没有设计用于改变感觉纤维范围的药物治疗， 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， 治疗，以重新建立神经支配稳态所需的缓解疼痛。感觉神经元有有限的 但在外周损伤后具有显著的生长能力。我们发现伤害感受器的生长速度 模式：1）轴突直接损伤后的再生-称为损伤再生（IR）和2）近端生长， 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-称为未受伤发芽 （美国）。利用转录组学技术，我们发现了3 '非翻译区（3'-UTR） 这两种生长模式之间的转录异构体。这些不同的3'-UTR表达模式是 预测促进与不同RNA结合蛋白（RBP）的物理相互作用。我们推测，美国和 IR是通过3'UTR的对比组之间的相互作用而区分的轴突生长的不同模式 同种型和调节这些转录物的不同RBP。 我们的长期目标是开发靶向生长模式特异性RBP的治疗方法，以改变不同形式的 在导致慢性疼痛的病理条件下失调的伤害感受器形态发生。到 为了实现这一目标，我们将确定RNA结合蛋白（RBP）在3'UTR中的作用 轴突生长不同模式中的亚型调控：损伤-再生（IR）和未损伤-发芽 （美国）。研究将分为三个目标。在目标1中，我们将确定限制性商业惯例在美国的作用，在目标2中，我们将 第三个目标是研究3'UTR亚型表达在IR中的作用。 坐骨神经挤压伤后的神经病理性疼痛。该提案测试了一种非常新颖的机制， 伤害感受纤维生长的调节。拟议的实验将阐明分子机制 潜在的不同模式的轴突生长（IR和US），可能有助于发展神经病理性 痛苦 !

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. !