THE EFFECTS OF GDNF ON PERIPHERAL NERVE REGENERATION

GDNF对周围神经再生的影响

• 批准号: 8606257
• 负责人: SUSAN E MACKINNON
• 金额: $ 48.83万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606257
• 关键词: Acute; Address; Allografting; Axon; Beds; Cell Proliferation; Chronic; Clinical; Cues; Denervation; Development; Distal; Down-Regulation; Drug Delivery Systems; Environment; Excision; Genes; Growth Factor; Injury; Lead; Location; Mediating; Methods; Modeling; Morbidity - disease rate; Motor; Motor Neurons; Muscle; Natural regeneration; Nerve; Nerve Growth Factor Receptors; Nerve Regeneration; Neurobiology; Neurons; Operative Surgical Procedures; Organ; Outcome; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral nerve injury; Phase; Physiological; Production; Proteins; Recovery; Recovery of Function; Regulation; Role; Schwann Cells; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Supporting Cell; Techniques; Technology; Testing; Tetracyclines; Therapeutic; Therapeutic Intervention; Time; Translations; United States; Upper Extremity; Viral Vector; Vision; axon growth; axon regeneration; cell motility; cell type; clinically relevant; design; disability; enhancing factor; functional outcomes; improved; migration; nerve gap; nerve injury; neurotrophic factor; overexpression; prevent; reconstruction; regenerative; reinnervation; repaired; response; therapy development

DESCRIPTION (provided by applicant): Severe peripheral nerve injuries are common and result in significant long-term functional morbidity. Despite recent advances in the understanding of the neurobiology related to nerve regeneration and refinement in surgical techniques, complete functional recovery after repair is rare. Extended regeneration times and delayed surgical reconstruction are two major factors in poor functional recovery. Exogenous delivery of growth factors (GFs) has the potential to address both of these barriers. In particular, glial derived neurotrophic factor (GDNF) is a potent motor neuron survival factor that enhances motor axon regeneration after chronic nerve injury. It is known that delivery of GDNF in the periphery (i.e. skeletal muscle) and site of nerve injury has a positive impact on peripheral nerve regeneration. However, the parameters (location, timing, and duration) for appropriate administration of GDNF as a therapeutic intervention for peripheral nerve injury and its effects on Schwann cells (SCs) are unknown. The unifying hypothesis of this proposal is that appropriate spatial and temporal regulation of exogenous GDNF in distal nerve and muscle will enhance functional recovery following long gap chronic peripheral nerve injury. The current proposal combines a drug delivery system, and viral vector technology to sequentially increase the levels of GDNF along the path of regenerating axons; at the sight of injury, in the distal nerve, and denervated muscle. Temporary delivery of GDNF from a drug delivery system will be used to enhance levels at the sight of injury to support the initial phase of axonal regeneration. Early phase overexpression of GDNF from SCs (that can be repressed by tetracycline induced gene excision) will provide increased GDNF levels in the distal nerve in the middle phase of regeneration (without axonal trapping), and late phase tetracycline-induced GDNF expression in the muscle will stimulate reinnervation of the muscle after prolonged denervation. Additionally, the proposal will systematically evaluate how SCs, the major support cell of the peripheral nervous system, respond to increased levels of GDNF after nerve injury and their role in GDNF-enhanced nerve regeneration. The aims of this proposal are: (1) To investigate the effect of spatially and temporally controlled GDNF using short term protein delivery at the site of injury and delayed, sequentially-induced delivery in the distal nerve and muscle to enhance recovery after chronic long nerve gap injury. (2) To determine the effect of increased GDNF levels on SCs and define their role in GDNF enhanced regeneration after peripheral nerve injury.

描述（由申请人提供）：严重的周围神经损伤很常见，并导致显着的长期功能发病率。尽管最近对与神经再生相关的神经生物学的理解和手术技术的改进取得了进展，但修复后完全功能恢复的情况很少见。再生时间延长和手术重建延迟是功能恢复不良的两个主要因素。外源性生长因子（GF）有可能解决这两个障碍。特别是，胶质源性神经营养因子（GDNF）是一种有效的运动神经元存活因子，可增强慢性神经损伤后运动轴突的再生。众所周知，在外周（即骨骼肌）和神经损伤部位输送 GDNF 对周围神经具有积极影响 再生。然而，适当施用 GDNF 作为周围神经损伤治疗干预的参数（位置、时间和持续时间）及其对雪旺细胞 (SC) 的影响尚不清楚。该提议的统一假设是，远端神经和肌肉中外源性 GDNF 的适当空间和时间调节将增强长间隙慢性周围神经损伤后的功能恢复。目前的提议结合了药物输送系统和病毒载体技术，沿着再生轴突的路径顺序增加 GDNF 的水平；当远端神经和失神经肌肉受伤时。从药物输送系统临时输送 GDNF 将用于提高损伤时的水平，以支持轴突再生的初始阶段。 SC 中 GDNF 的早期过度表达（可以通过四环素诱导的基因切除来抑制）将在再生中期（无轴突捕获）中增加远端神经中的 GDNF 水平，而肌肉中的晚期四环素诱导的 GDNF 表达将在长期去神经后刺激肌肉的神经支配。此外，该提案还将系统地评估 SC（周围神经系统的主要支持细胞）如何对神经损伤后 GDNF 水平升高做出反应，以及它们在 GDNF 增强神经再生中的作用。该提案的目的是：（1）研究空间和时间控制的 GDNF 的效果，在损伤部位使用短期蛋白质递送，并在远端神经和肌肉中延迟、顺序诱导递送，以促进慢性长神经间隙损伤后的恢复。 (2)确定GDNF水平升高对SC的影响，并明确其在周围神经损伤后GDNF增强再生中的作用。