Dorsal root injury and repair

描述(申请人提供)：由背根损伤损伤的初级感觉神经轴突不能再生到脊髓，导致慢性疼痛和永久性感觉丧失。阻止CNS-PNS界面即背根进入区(DREZ)再生的机制尚不清楚。目前克服这种再生失败的方法只取得了有限的成功。在过去的几年里，我们率先应用活体成像来直接监测到达DREZ的活体小鼠的感觉神经轴突。这些研究让我们假设，再生失败和目前干预措施有限的成功可能是因为再生轴突经历了快速和异常的突触分化，导致DRIZ的生长过早停止。为了测试这一想法，我们将应用先进的技术，包括体内成像、可诱导的转基因小鼠和靶向电子显微镜。在目标1中，我们将通过测试NG2胶质细胞是否诱导突触前分化和/或生长停滞来确定突触后机制。在目标2中，我们将通过测试靶向钙通道α2Delta亚基及其与凝血酶反应蛋白的相互作用是否会促进再生来确定突触前机制。在目标3中，我们将通过联合使用加巴喷丁(GBP)和普瑞巴林(PG)(阻止突触发生)与针对内源性和外源性生长障碍的常规干预措施来促进强大的再生，这些障碍单独引起的再生很少。这项拟议的工作有可能修改对初级感觉神经元再生失败的普遍解释，也可能适用于脊髓损伤。此外，GBP和PG是FDA已经批准的常用的抗神经病理性疼痛药物。因此，我们的工作可以迅速应用于臂丛、腰骶丛和马尾神经损伤的患者，这些损伤是常见的，使人虚弱，没有有效的治疗方法。

DESCRIPTION (provided by applicant): Primary sensory axons injured by dorsal root injuries fail to regenerate into the spinal cord, leading to chronic pain and permanent sensory loss. The mechanisms that prevent regeneration at the CNS-PNS interface, the dorsal root entry zone (DREZ), are unknown. The present approaches for overcoming this regeneration failure have had only limited success. Over the past few years, we have pioneered in applying in vivo imaging to directly monitor sensory axons arriving at the DREZ in living mice. These studies lead us to hypothesize that the regeneration failure and the limited success with current interventions might be because regenerating axons undergo rapid and aberrant synaptic differentiation that causes growth to cease prematurely at the DREZ. To test this idea, we will apply advanced techniques, including in vivo imaging, inducible transgenic mice, and targeted electron microscopy. In Aim 1, we will identify postsynaptic mechanisms by testing whether NG2 glia induce presynaptic differentiation and/or growth arrest. In Aim 2, we will identify presynapti mechanisms by testing whether targeting calcium channel alpha2delta subunits and their interaction with thrombospondins will promote regeneration. In Aim 3, we will promote robust regeneration by combining treatment with gabapentin (GBP) and pregabalin (PG), which prevent synaptogenesis, with conventional interventions targeting intrinsic and extrinsic growth barriers, which individually elicit little regeneration. The proposed work has the potential to revise the prevailing explanation for the regeneration failure of primary sensory neurons and may also be applicable to spinal cord injury. In addition, GBP and PG are commonly prescribed anti-neuropathic pain medications already approved by the FDA. Our work therefore can be quickly applied to patients with brachial plexus, lumbosacral plexus and cauda equina injuries, which are common and debilitating and have no effective treatment.