Dorsal root injury and repair

背根损伤与修复

基本信息

批准号：
8578475
负责人：
YOUNG-JIN SON
金额：
$ 33.91万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8578475
关键词：
Ablation Afferent Neurons Analgesics Astrocytes Axon Behavioral Binding Brachial plexus structure CSPG4 gene Calcium Channel Caliber Cauda Equina Cells Clinical Coculture Techniques Combined Modality Therapy Differentiation and Growth Electron Microscopy Environment FDA approved Failure Figs - dietary Glutamates Growth Growth Inhibitors Image In Vitro Injury Intervention Investigation Knockout Mice Knowledge Lead Life Light Lumbosacral plexus structure Mediating Monitor Mus Natural regeneration Neuroglia Neurons Neurotrophin 3 Patients Pharmaceutical Preparations Proprioception Recovery of Function Regimen Resistance Role Sensory Signal Transduction Spinal Cord Spinal Injuries Spinal cord injury Spinal nerve root structure Swelling Synapses Techniques Testing Thrombospondin 1 Thrombospondins Transgenic Mice Work axon regeneration cell motility chronic neuropathic pain chronic pain combinatorial conventional therapy effective therapy gabapentin human FRAP1 protein in vivo injured injury and repair innovation insight nanoparticle neurotrophic factor novel painful neuropathy postsynaptic pregabalin presynaptic prevent public health relevance spinal nerve posterior root success synaptogenesis therapy design tomography trafficking voltage

项目摘要

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.

描述（由申请人提供）：背根损伤受伤的主要感觉轴突无法再生到脊髓中，导致慢性疼痛和永久性感觉丧失。在CNS-PNS界面，背根进入区（DREZ）上预防再生的机制是未知的。目前克服这种再生失败的方法只有有限的成功。在过去的几年中，我们率先应用体内成像，直接监测活着的小鼠到达Drez的感觉轴突。这些研究导致我们假设，再生轴突经历了快速和异常的突触分化，导致生长在DREZ中过早停止，因此再生的再生失败和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。为了测试这个想法，我们将应用先进的技术，包括体内成像，诱导的转基因小鼠和靶向电子显微镜。在AIM 1中，我们将通过测试NG2 Glia是否诱导突触前分化和/或生长停滞来确定突触后机制。在AIM 2中，我们将通过测试靶向钙通道α2DELTA亚基及其与血小板传播的相互作用是否会促进再生来鉴定出突变的机制。在AIM 3中，我们将通过将治疗与Gabapentin（GBP）和gababalin（PG）相结合，以防止突触发生，并与针对固有和外在生长障碍的常规干预措施相结合，从而促进了稳健的再生，从而可以单独产生几乎没有再生。拟议的工作有可能修改原发性神经元再生失败的主要解释，并且也可能适用于脊髓损伤。此外，GBP和PG通常是FDA已批准的抗神经性止痛药。因此，我们的工作可以快速应用于臂丛神经，腰c和cauda equina损伤的患者，这些患者常见且令人衰弱，没有有效的治疗。