Mechanisms of Functional Recovery After Partial Nerve Injury

描述(由申请人提供)： 在战斗军人和退伍军人中，神经损伤是导致永久性神经残疾的常见原因。众所周知，神经损伤的受害者遵循高度不同的临床轨迹。一些患者完全康复了，但很大一部分患者未能恢复正常功能。不幸的是，没有任何治疗方法可以提高恢复神经功能的机会。大量的工作集中在促进神经损伤后轴突的再生。相比之下，人们对神经系统在神经损伤后如何进行功能补偿知之甚少；因此，功能补偿是减少神经损伤所致残疾的一条被低估的途径。我们建议在动物模型中进行研究，以证明激素受体调节在促进功能恢复方面的有效性，而不需要轴突生长。在前期工作中，我们展示了一个研究无轴突再生的功能性神经元恢复的模型系统。正常情况下，双侧颈上神经节(SCG)均支配松果体以刺激夜间褪黑激素的合成。在Fischer 344(F344)大鼠中，当我们移除一个SCG(1xSCGx)时，褪黑素下降到基础水平的50%；在这种下降之后的第二天，褪黑素自发恢复到基础水平的100%，这表明在没有轴突再生的情况下，神经回路的功能恢复发生。在携带盐皮质激素受体(MR)功能突变的棕色挪威(BN)大鼠中，褪黑激素水平立即下降，无法改善。当BN大鼠接受皮质类固醇或MR拮抗剂治疗时，大鼠褪黑素的合成迅速而永久地恢复。这些研究表明，神经回路可以在没有轴突生长的情况下自发恢复正常功能，作用于MR或糖皮质激素受体(GR)的类固醇能够促进神经功能的恢复。在这个方案中，我们将检验MR拮抗剂和GR激动剂在神经元损伤后的特定时间内使用时促进功能恢复的核心假设；我们进一步假设神经元损伤后MR和GR的调节改变了对神经损伤的最佳补偿所需的炎症反应。将测试以下具体目标。在目标1中，我们将测试MR拮抗剂用于促进部分神经损伤后神经恢复的时间进程。在目标2中，我们将测试GR激动剂用于促进部分神经损伤后神经恢复的时间进程。最后，在目标3中，我们将测试炎性细胞因子在部分神经损伤后功能恢复中的作用。我们假设特定细胞因子的级联反应是靶组织失神经的结果，保护性细胞因子反应是由类固醇激素调节的转录驱动的，并与长期功能恢复相关。这些实验有望为神经损伤的潜在临床治疗确定时间窗口，并将识别促进周围神经损伤后功能恢复的分子标志物和信号通路。

DESCRIPTION (provided by applicant): Nerve injury is a common cause of permanent neurological disability in the combat military and veterans. It is well-known that victims of nerve injury follow highly variable clinical trajectories. Some patients make a full recovery, yet a very large number fail to regain normal function. Unfortunately, there are no treatments that improve chances to restore neurological function. A great deal of work has focused on encouraging axonal regrowth after nerve injury. In contrast, very little is known about how the nervous system functionally compensates after nerve damage; functional compensation therefore represents an underappreciated pathway to reducing disability from nerve injuries. We propose studies in animal models to demonstrate the efficacy of hormone receptor modulation for enhancing functional recovery without axonal growth. In preliminary work, we demonstrate a model system to study functional neuronal recovery without axon regeneration. Normally, the bilateral superior cervical ganglia (SCG) both innervate the pineal gland to stimulate nightly melatonin synthesis. In Fischer 344 (F344) rats, when we remove one SCG (1xSCGx), melatonin falls to 50% of basal levels; the day after this drop, melatonin spontaneously returns to 100% of basal levels, indicating functional recovery of the neural circuit occurs in the absence of axon regrowth. In Brown Norway (BN) rats, which carry a gain of function mutation in the mineralocorticoid receptor (MR), melatonin levels fall immediately and fail to make improvements. When BN rats are treated with corticosteroids or with antagonists of MR, rats make a rapid and permanent recovery in melatonin synthesis. These studies indicate that a neural circuit can spontaneously recover normal function without axon growth, and that steroids that act on MR or the glucocorticoid receptor (GR) are capable of enhancing functional neurological recovery. In this proposal, we will test the core hypothesis that MR antagonists and GR agonists promote function recovery when administered during specific periods after neuronal injury; we further hypothesize that MR and GR modulation after neuronal injury modifies the inflammatory response that is required for optimal compensation to neurological injury. The following specific aims will be tested. In Aim 1, we will test the time course of administration of MR antagonists for enhancing neurological recovery after partial nerve injury. In Aim 2, we will test the time course of administration of GR agonists for enhancing neurological recovery after partial nerve injury. Finally, in Aim 3, we will test the role of inflammatory cytokines on functional recovery from partial nerve injury. We hypothesize that a cascade of specific cytokines results from denervation of target tissue and that protective cytokine responses are driven by steroid hormone regulated transcription and correlate with long term functional recovery. These experiments promise to define time windows for potential clinical treatment of nerve injury and will identify molecular markers and signaling pathways that promote functional recovery after peripheral nerve injury.