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: 7693089
• 负责人: H Richard Koerber
• 金额: $ 33.14万
• 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 2009-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7693089
• 关键词: ASIC channel; Address; Affect; Afferent Neurons; Causalgia; Cell physiology; Cutaneous; Development; Discrimination; Esthesia; Evaluation; Event; Fiber; GDNF gene; Gene Expression; Genes; Goals; Heating; Hyperesthesia; Hypersensitivity; Individual; Lead; Mechanics; Mediating; Messenger RNA; Methods; Molecular; Mus; NTF3 gene; Natural regeneration; Nerve; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Nerve Regeneration; Neurons; Neurotrophin 3; Nociceptors; Numbers; Pain; Peripheral; Peripheral Nerves; Peripheral nerve injury; Pharmacologic Substance; Population; Preparation; Prevention; Procedures; Process; Property; Protein Overexpression; Proteins; Quality of life; Range; Recovery; Recovery of Function; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory; Series; Signal Transduction; Skin; Small Interfering RNA; Spinal Cord; Stimulus; Symptoms; Syndrome; TRPV1 gene; Techniques; Testing; Time; Tissues; Transfection; Trophic Factor Receptor; Western Blotting; abstracting; allodynia; chronic pain; improved; in vivo; insight; mRNA Expression; nerve injury; novel; receptor; reinnervation; research study; sensory stimulus

Abstract Clinically peripheral nerve injury and regeneration is a common occurrence. Normal regeneration results in faulty localization of stimuli, increased two point discrimination thresholds and general hypersensitivity, ranging from relativity innocuous hyperesthesia often described as unusual or vivid sensations to allodynia or causalgia which are debilitating painful sensations often elicited by innocuous cutaneous stimuli. Although most of these symptoms show improvement with time, others most notably the pain syndromes can last for years and greatly affect an individual¿s quality of life. Our major goal in this proposal is to understand the cellular processes that underlie plasticity in sensory neurons following peripheral nerve injury. Specifically, we will look at the effects of target-derived trophic factor signaling induced plasticity of primary sensory neurons reinnervating the skin. We have now shown that many types of regenerated cutaneous afferent fibers show increased sensitivity following regeneration. In another series of studies we examined the effects of overexpression of trophic factors in the skin. Depending on the factor expressed we found that different types of cutaneous sensory neurons were sensitized to mechanical and thermal stimuli. In addition we found that there was an increase in specific combinations of receptors/channels that are believed to be involved in the transduction of peripheral stimuli by sensory neurons (e.g. TRP and ASIC channels). Finally, we found that the expression of these same trophic factors and receptors/channels is increased in the DRG and skin respectively following nerve injury. We hypothesize that the increase in trophic signaling results in the increased expression of several TRP and ASIC channels in regenerating cutaneous fibers resulting in an increased sensitivity to peripheral stimuli. Here we propose to use a novel in vivo siRNA procedure which allows us to knockdown the expression of individual receptor/channels specifically in the regenerating cutaneous fibers and an ex vivo recording preparation to directly test this hypothesis. Evaluation of our hypotheses and the determination of the specific signaling events 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 functional recovery following regeneration as well as, alleviation of the adverse symptoms and potential chronic pain syndromes.

摘要 临床上，周围神经损伤和再生是常见病。正常再生 结果刺激定位错误，两点辨别阈值升高，一般 从相对论到无伤大雅的感觉过敏，常被描述为不寻常的或鲜活的感觉 痛觉超敏或灼痛，通常由无害的皮肤刺激引起，使人虚弱的痛感。 虽然大多数这些症状随着时间的推移而改善，但其他最明显的疼痛综合征可能 经年累月，极大地影响着S个人的生活质量。我们在这项建议中的主要目标是了解 周围神经损伤后感觉神经元可塑性的细胞过程。具体来说， 我们将观察靶源营养因子信号对初级感觉可塑性的影响。 对皮肤重新进行神经支配的神经元。 我们现在已经表明，许多类型的再生皮肤传入纤维显示增加 再生后的灵敏度。在另一系列研究中，我们检查了过度表达的影响 皮肤中的营养因子。根据表达的因素，我们发现不同类型的皮肤 感觉神经元对机械刺激和热刺激敏感。此外，我们发现有一个 被认为参与转导的受体/通道的特定组合增加 感觉神经元的外周刺激(如Trp和ASIC通道)。最后，我们发现， 这些相同的营养因子和受体/通道分别在背根节和皮肤中增加 神经损伤。 我们假设，营养信号的增加导致了几个基因表达的增加 再生皮肤纤维中的Trp和ASIC通道导致对外周的敏感性增加 刺激物。在这里，我们建议使用一种新的体内siRNA程序，它允许我们敲除表达 单个受体/通道在再生皮肤纤维中的特异性和体外记录 为直接检验这一假设做准备。对我们的假设的评估和对具体假设的确定 负责这些纤维敏化的信号事件受体/通道将提供新的见解 这些工艺，更重要的是，可以为制药的发展提供潜在的目标 治疗。这些新疗法也可以改善再生后的功能恢复。 AS，缓解不良症状和潜在的慢性疼痛综合征。