THE EFFECTS OF GDNF ON PERIPHERAL NERVE REGENERATION

描述（由申请人提供）：严重的周围神经损伤是常见的，并导致显著的长期功能障碍。尽管最近对神经再生和外科技术改进的神经生物学的理解有所进展，但修复后完全功能恢复是罕见的。延长再生时间和延迟手术重建是功能恢复不良的两个主要因素。生长因子（GFs）的外源性递送有可能解决这两个障碍。特别是，神经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，可促进慢性神经损伤后运动轴突的再生。已知外周（即骨骼肌）和神经损伤部位递送GDNF对周围神经有积极影响

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.