Peripheral Nerve Regeneration and Sensory Neuron Plasticity

周围神经再生和感觉神经元可塑性

• 批准号: 9087050
• 负责人: H Richard Koerber
• 金额: $ 39.55万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087050
• 关键词: Acute; Afferent Neurons; C Fiber; Cell Separation; Cell physiology; Cells; Characteristics; Clinical; Cutaneous; Cutaneous Muscle; Development; Disease; Exhibits; Fiber; Gene Expression; Goals; Health; Heating; Histocompatibility Testing; Individual; Injury; Lead; Life; Mechanical Stimulation; Mechanics; Mediating; Messenger RNA; Methods; Molecular; Molecular Profiling; Mus; Muscle; Muscle Fibers; Natural regeneration; Nerve; Nerve Regeneration; Nociception; Nociceptors; P2X-receptor; Peripheral; Peripheral Nerves; Peripheral nerve injury; Persistent pain; Pharmacologic Substance; Phenotype; Population; Population Heterogeneity; Preparation; Process; Property; Public Health; Purinoceptor; Recovery of Function; Reverse Transcriptase Polymerase Chain Reaction; Role; Skin; Small Interfering RNA; Spinal Cord; Stimulus; Striated Muscles; Symptoms; Syndrome; TRPV1 gene; Techniques; Testing; Time; chronic neuropathic pain; chronic pain; functional plasticity; improved; in vivo; innovation; insight; knock-down; nerve injury; novel; novel strategies; novel therapeutics; painful neuropathy; peripheral nerve regeneration; receptor; reinnervation; response

DESCRIPTION (provided by applicant): Chronic pain following acute peripheral nerve injury is a major public health issue. Our primary goal in this proposal is to understand the cellular processes that underlie plasticity in cutaneous and muscle sensory neurons following injury and regeneration. Specifically, we will look at injury-induced plasticity of primary sensory neurons reinnervating either skin or striated muscle. In the first aim, we use ex vivo skin or muscle/nerve/DRG/spinal cord preparations and our novel method for recovering individual functionally characterized sensory neurons to determine the comprehensive phenotypes of cutaneous C-fibers and Group IV muscle afferents in naive mice. This includes characterization of the gene expression profiles of the individual functionally characterized fibers. In our preliminary studies we have indentified several unique functional classes of these fibers. In the second aim, we will first examine the effects of nerve injury on the functional properties and correlated changes in gene expression in individual characterized fibers reinnervating skin or muscle. In our preliminary studies we have confirmed and expanded upon earlier studies showing that these fibers are sensitized following regeneration. In addition, our results suggest that some fibers are changing phenotype. Next we will examine changes in DRG expression of specific trk, GFRalpha, ASIC, TRP and purinergic receptors/channels contained in these fibers to indentify possible molecular mechanisms responsible for the changes in function observed following nerve injury and regeneration. In the third aim, we will use our novel in vivo siRNA knockdown technique to test the hypothesis that the injury-induced increase in the expression of particular receptors/channels (e.g. ASIC, TRP and purinergic) mediates the observed functional plasticity in specific populations of cutaneous and muscle afferents. For example, we expect to find that knockdown of the increase in TRPM3 expression levels following cutaneous nerve injury and regeneration will block the observed sensitization of cutaneous C-polymodal fibers to heat. Similarly we expect that knockdown in ASIC3 expression following muscle nerve injury and regeneration will block the sensitization of muscle afferents to mechanical stimulation. The determination of the specific receptors/channels responsible for sensitization of these fibers will provide new insights to these processes and more importantly could provide potential targets for the development of pharmaceutical therapies. These new therapies could provide for improved treatments for the alleviation of the adverse symptoms of chronic neuropathic pain.

描述（由申请人提供）：急性周围神经损伤后的慢性疼痛是一个主要的公共卫生问题。我们的主要目标是在这个建议是了解细胞的过程，在皮肤和肌肉感觉神经元损伤和再生后的可塑性。具体来说，我们将着眼于损伤诱导的可塑性的初级感觉神经元重新支配皮肤或横纹肌。 在第一个目标中，我们使用离体皮肤或肌肉/神经/DRG/脊髓制剂和我们的新方法，用于恢复个体功能特征的感觉神经元，以确定在幼稚小鼠中皮肤C-纤维和第IV组肌肉传入的综合表型。这包括表征单个功能表征纤维的基因表达谱。在我们的初步研究中，我们已经确定了这些纤维的几个独特的功能类别。 在第二个目标中，我们将首先研究神经损伤对功能特性的影响，以及在重新支配皮肤或肌肉的单个特征纤维中基因表达的相关变化。在我们的初步研究中，我们已经证实并扩展了早期的研究，表明这些纤维在再生后会被致敏。此外，我们的研究结果表明，一些纤维正在改变表型。接下来，我们将研究DRG中特定trk、GFR α、ASIC、TRP和这些纤维中所含嘌呤能受体/通道表达的变化，以确定可能的分子机制，这些机制负责神经损伤和再生后观察到的功能变化。 在第三个目标中，我们将使用我们的新的体内siRNA敲低技术来测试损伤诱导的特定受体/通道（例如ASIC、TRP和嘌呤能）表达的增加介导了在特定群体的皮肤和肌肉传入中观察到的功能可塑性的假设。例如，我们期望发现在皮肤神经损伤和再生后TRPM 3表达水平增加的敲低将阻断所观察到的皮肤C-多模态纤维对热的敏感性。类似地，我们预期在肌肉神经损伤和再生后ASIC 3表达的敲低将阻断肌肉传入对机械刺激的敏化。 确定负责这些纤维致敏的特异性受体/通道将 为这些过程提供了新的见解，更重要的是可以为药物治疗的发展提供潜在的目标。这些新的疗法可以提供用于缓解慢性神经性疼痛的不良症状的改进的治疗。