THE EFFECTS OF GDNF ON PERIPHERAL NERVE REGENERATION

GDNF对周围神经再生的影响

基本信息

批准号：
8417657
负责人：
SUSAN E MACKINNON
金额：
$ 44.53万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/8417657
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

项目摘要

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。尽管了解与神经再生和手术技术的完善有关的神经生物学的了解最近取得了进步，但修复后的完全功能恢复很少。延长的再生时间和延迟的手术重建是功能恢复不良的两个主要因素。生长因子（GFS）的外源输送有可能解决这两个障碍。特别是，神经胶质衍生的神经营养因子（GDNF）是一种有效的运动神经元存活因子，可在慢性神经损伤后增强运动轴突再生。众所周知，GDNF在外围（即骨骼肌）和神经损伤部位的递送对外围神经具有积极影响再生。但是，适当地施用GDNF作为外周神经损伤及其对Schwann细胞（SCS）的影响的参数（位置，时间和持续时间）尚不清楚。该提案的统一假设是，在长差距慢性外周神经损伤后，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功能恢复。当前的提案结合了药物输送系统，病毒载体技术沿沿轴突再生的路径依次提高GDNF的水平；在受伤时，在远端神经和肌肉中。从药物输送系统中暂时递送GDNF将用于增强受伤的水平，以支持轴突再生的初始阶段。 SCS的GDNF的早期过度表达（可以被四环素诱导的基因切除抑制）将在再生中间（无轴突诱捕）中提供远端神经中的GDNF水平，而后期四环素后期诱导的GDNF诱导的GDNF在肌肉中的GDNF表达会刺激肌肉的重新促进肌肉的延长。此外，该提案将有系统地评估周围神经系统的主要支持细胞SC对神经损伤后的GDNF水平的响应及其在GDNF增强神经再生中的作用。该提案的目的是：（1）使用短期蛋白质在损伤部位进行短期蛋白质递送，并在远端神经和肌肉中延迟，延迟诱导的递送，以增强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，并确定其在周围神经损伤后增强GDNF的作用。