MECHANISMS OF PREFERENTIAL MOTOR REINNERVATION

描述：(改编自《调查者摘要》)：本报告的目标 研究是为了改善周围神经修复的结果。我们的战略是 基于这一发现，再生运动神经轴突优先重新神经支配 肌肉和/或肌肉神经，一种称为优先运动神经再支配的过程 (PMR)。之前的实验工作提出了修剪假说： 再生的运动轴突会产生多个侧枝发芽， 随机地重新支配以前的感觉或运动性雪旺细胞管。 随着时间的推移，通过修剪侧支产生特定的投影 皮肤通路，同时维持肌肉通路。运动神经元 因此，最初对两条路径进行采样的路径被转换为投影到 肌肉。仅限于皮肤通路的运动神经元没有矫正的方法 他们的错误，他们的数量保持不变。 随后的实验评估了通路和终末器官对 PMR。自然产生的特异性变异被认为是对 通路年龄和神经元年龄。这个实验发现有很好的相关性。 周围神经修复常恢复的临床观察 幼儿的功能正常，但成年人的功能却不正常。特异性 可能被神经修复部位近端的前一次挤压或 在修复过程中只需电刺激一小时。这个 后一种观察结果令人兴奋，有两个原因：1)特异性的增加 伴随着再生速度的戏剧性增加，以及2) 技术不仅是一种研究工具，而且可以很容易地应用于临床 无需植入装置或延长时间的神经修复 治疗。 这些实验评估了轴突群体的行为，定义了 修改再生专一性的变量。目前的提案描述了 从自然历史观察到自然历史观察的下一步 治疗策略的制定：确定治疗的分子基础 专一性生成。我们选择了两个变量最大的 对通路的影响(感觉与运动，预变性)和对神经元的影响 (年龄，电刺激)，并将操纵它们来检查 对通路和神经元的分子后果。其他目标将进一步 探索电刺激的机制和后果，并评估 运动通路标志物L2碳水化合物在特异性中的作用 一代。

DESCRIPTION: (Adapted from the Investigator's Abstract): The goal of this research is to improve the outcome of peripheral nerve repair. Our strategy is based on the discovery that regenerating motor axons preferentially reinnervate muscle and/or muscle nerve, a process termed Preferential Motor reinnervation (PMR). Previous experimental work suggested the pruning hypothesis: regenerating motor axons generate multiple collateral sprouts, which reinnervate previously sensory or motor Schwann cell tubes on a random basis. Over time, specific projections are generated by pruning collaterals from cutaneous pathways while maintaining those in muscle pathways. A motoneuron that initially samples both pathways is thus converted to one projecting to muscle. Motoneurons limited to cutaneous pathways have no means of correcting their error, and their number remains constant. Subsequent experiments evaluated the contributions of pathway and end organ to PMR. Naturally occurring variations in specificity were seen in response to both pathway age and neuronal age. This experimental finding correlated well with the clinical observation that peripheral nerve repair often restores normal function in young children but never does so in adults. Specificity could be manipulated by previous crush proximal to the site of nerve repair or by electrical stimulation for only one hour during the repair itself. The latter observation is exciting for two reasons:1) the increase in specificity was accompanied by a dramatic increase in regeneration speed, and 2) the technique is not only a research tool, but could be readily applied to clinical nerve repair without the need for implantation of a device or prolonged treatment. These experiments have evaluated the behavior of axon populations, defining the variables that modify regeneration specificity. The current proposal describes the next step in the progression from natural history observation to the formulation of treatment strategies: definition of the molecular basis of specificity generation. We have chosen the two variables with the greatest impact on the pathway (sensory vs. motor, predegeneration) and on the neuron (age, electrical stimulation), and will manipulate them to examine the molecular consequences for the pathway and neuron. Additional aims will further explore the mechanism and consequences of electrical stimulation, and evaluate the role of a motor pathway marker, the L2 carbohydrate, in specificity generation.