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: 7728498
• 负责人: H Richard Koerber
• 金额: $ 32.57万
• 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 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728498
• 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 Regeneration; Neurons; Nociceptors; Pain; Peripheral; Peripheral Nerves; Peripheral nerve injury; Pharmacologic Substance; Population; Preparation; Prevention; Procedures; Process; Property; Proteins; Quality of life; 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; allodynia; chronic pain; improved; in vivo; insight; knock-down; mRNA Expression; nerve injury; novel; overexpression; public health relevance; receptor; reinnervation; research study

DESCRIPTION (provided by applicant): 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 re-innervating 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 knock down the expression of individual receptors/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. PUBLIC HEALTH RELEVANCE Peripheral nerve injury and subsequent regeneration often leads to a variety of sensory deficits including chronic pain syndromes. In this application we are proposing to determine specific cellular and molecular changes in sensory neurons that could lead to these symptoms. Determination of these mechanisms could provide targets for new pharmaceutical therapies that could provide for improved functional recovery following regeneration as well as alleviation of the adverse syndromes.

描述（由申请人提供）：临床上周围神经损伤和再生是常见的情况。正常的再生导致刺激的错误定位、增加的两点辨别阈值和全身超敏反应，范围从通常被描述为不寻常或生动的感觉的相对无害的感觉过敏到异常性疼痛或头痛，异常性疼痛或头痛是通常由无害的皮肤刺激引起的使人衰弱的疼痛感觉。虽然这些症状中的大多数随着时间的推移而有所改善，但其他症状，尤其是疼痛综合征，可能持续数年，并极大地影响个人的生活质量。我们本提案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，我们将研究靶源性营养因子信号传导诱导的初级感觉神经元重新支配皮肤的可塑性的影响。我们现在已经表明，许多类型的再生皮肤传入纤维显示出增加的敏感性再生后。在另一系列研究中，我们检查了皮肤中营养因子过度表达的影响。根据所表达的因子，我们发现不同类型的皮肤感觉神经元对机械和热刺激敏感。此外，我们发现，有一个特定的组合的受体/通道，被认为是参与外周刺激的感觉神经元（如TRP和ASIC通道）的转导增加。最后，我们发现这些相同的营养因子和受体/通道的表达在神经损伤后分别在DRG和皮肤中增加。我们推测营养信号的增加导致再生皮肤纤维中几种TRP和ASIC通道的表达增加，从而导致对外周刺激的敏感性增加。在这里，我们建议使用一种新的体内siRNA程序，使我们能够敲低个别受体/通道的表达，特别是在再生的皮肤纤维和离体记录准备直接测试这一假设。我们的假设的评估和特定的信号事件的受体/通道负责这些纤维的敏化的确定将提供新的见解，这些过程，更重要的是可以提供潜在的药物治疗的发展目标。这些新的疗法可以在再生后提供改善的功能恢复，以及减轻不良症状和潜在的慢性疼痛综合征。周围神经损伤和随后的再生通常会导致各种感觉缺陷，包括慢性疼痛综合征。在本申请中，我们提出确定可能导致这些症状的感觉神经元中的特定细胞和分子变化。这些机制的确定可以为新的药物治疗提供靶点，这些药物治疗可以在再生后提供改善的功能恢复以及减轻不良综合征。