Enhancing Motor Neuron Regeneration Accuracy

描述(申请人提供)：优先运动神经再支配(PMR)是指在混合周围神经中再生运动神经元，将远端神经分支重新支配到肌肉而不是皮肤。研究PMR的一个有用模型是啮齿类动物的股神经。在腿部近端，运动轴突散布在整个混合神经中。 神经远端分成两个大致相等的终末分支，一个是到股四头肌的运动支，另一个是作为隐神经延续的纯感觉支。许多实验室以前的工作表明，在近端损伤后，再生的运动神经元优先(尽管不完全)重新支配末端股四头肌分支(到肌肉)而不是隐支(到皮肤)。在我们最近对PMR的研究过程中，我们做了一个令人惊讶的观察：来自失神经肌肉的信息显然迅速地传递到近端神经损伤部位，并影响随后运动神经元再生的准确性。我们有初步的数据表明，肌肉传递这一信息依赖于主动的逆行轴突运输，这种运输在远端失神经持续约30小时，或直到轴突经历沃勒变性。这项建议中的实验建立在这一意外观察的基础上，并将阐明逆行对失神经的影响。 肌肉运输是影响PMR的一种机制。我们将使用各种具有良好特性的啮齿类动物股神经手术模型来实现我们的特定目标。公共卫生相关性：尽管再生，但广泛的周围神经损伤可导致整个肢体或肢体远端(如手)的有效瘫痪。周围神经系统神经损伤后功能恢复的主要关键是轴突准确地再生到其原始的靶终末器官。这项拟议的研究利用了啮齿类动物的股神经，并将评估运动神经元投射回其原始终末神经分支的准确性。

DESCRIPTION (provided by applicant): Preferential motor reinnervation (PMR) refers to the preference of regenerating motor neurons in a mixed peripheral nerve to reinnervate a distal terminal nerve branch to muscle rather than skin. A useful model to study PMR is the rodent femoral nerve. Proximally in the leg, motor axons are dispersed across the entire mixed nerve. Distally, the nerve divides into two approximately equal terminal branches; a motor branch to the quadriceps muscle and a purely sensory branch which continues as the saphenous nerve. Much previous work from several laboratories has shown that following a proximal lesion regenerating motor neurons preferentially, albeit incompletely, reinnervate the terminal quadriceps branch (to muscle) versus the saphenous branch (to skin). During the course of our recent studies on PMR we made a surprising observation: information from the denervated muscle is apparently rapidly conveyed to the proximal nerve lesion site and influences the subsequent accuracy of motor neuron regeneration. We have preliminary data suggesting that the delivery of this information from muscle is dependent upon active retrograde axonal transport which continues in distal denervated nerve for approximately 30 hours, or until the axon undergoes Wallerian degeneration. The experiments in this proposal build upon this unexpected observation, and will clarify the influence in denervated nerve of retrograde transport from muscle as a mechanism that influences PMR. We will use a variety of well characterized surgical models of the rodent femoral nerve to accomplish our specific aims. PUBLIC HEALTH RELEVANCE: Despite regeneration, extensive peripheral nerve injuries can result in the effective paralysis of the entire limb or distal portions of the limb such as the hands. The major key to recovery of function following nerve lesions in the peripheral nervous system is the accurate regeneration of axons to their original target end-organs. The proposed studies utilize the rodent femoral nerve and will assess the accuracy with which motor neurons project back to their original terminal nerve branch.