Multipronged approach to promote functional axonal regeneration in the spinal cord after injury

多管齐下促进脊髓损伤后功能性轴突再生

基本信息

批准号：
10767236
负责人：
Veronica Jean Tom
金额：
$ 7.83万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10767236
关键词：
Acetylation Adult Affect American Automobile Driving Axon Back Behavioral Central Nervous System Cervical spinal cord injury Chondroitin ABC Lyase Chondroitinases Cicatrix Clozapine Crush Injury Cytoskeleton Data Digestion Disparate Environment FRAP1 gene Fostering Genetic Goals Growth Guanosine Triphosphate Phosphohydrolases In Vitro Injury Kinesin Lead Length Mediating Methods Microtubules Modeling Motor Multiple Trauma Natural regeneration Neurons Oxides Peripheral Nerves Play Population Proteins Public Health Ras homolog enriched in brain Recovery Recovery of Function Recurrence Role Sensorimotor functions Sensory Spinal Spinal Cord Spinal Ganglia Spinal cord injury Structure Synapses Testing Therapeutic Transplantation Vertebral column axon growth axon regeneration constitutive expression designer receptors exclusively activated by designer drugs dorsal column experimental study gray matter improved in vitro Model in vivo knock-down new therapeutic target novel therapeutic intervention novel therapeutics permissiveness repaired response spinal nerve posterior root therapeutic target

项目摘要

PROJECT SUMMARY The lack of successful regeneration after injury in the mature central nervous system is due to intrinsic and environmental obstacles. Though progress in the field has been made, overcoming these barriers to result in robust functional axon regeneration and recovery is still a significant challenge. We build upon preliminary data and hypothesize that recurrent DREADD-mediated neuronal activation after injury is a means to enhance functional axon regeneration. Additionally, we will test the hypothesis that neuronal activation increases axon regeneration via both mTOR activation and increasing dynamic microtubules. We will these our hypotheses both in vitro using adult dorsal root ganglion neuron cultures and in vivo using dorsal root crush, dorsal columns spinal cord injury (SCI)/peripheral nerve graft (PNG), and incomplete cervical SCI/PNG models. In Aim 1, we will elucidate how repeated, chemogenetic neuronal activation enhances axon regeneration. In Aim 2, we will assess if neuronal activation – alone or in combination with manipulations that increase dynamic microtubules and mTOR activation – promotes functional axon regeneration. Collectively, we will: 1) elucidate mechanisms behind how neuronal activation enhances growth, potentially identifying new therapeutic targets; 2) determine the extent to which neuronal activation enhances regeneration in different injury models (dorsal root crush, SCI); 3) determine if neuronal activation has disparate or similar effects in different populations of neurons (DRG vs. CNS); 4) test whether meaningful axonal regeneration is facilitated using a unique, multi-faceted approach that: a) uses chemogenetic neuronal activation – possibly along with further increasing dynamic microtubules and/or mTOR activation – to enhance the axonal growth response; b) provides a more growth-permissive environment after an injury (i.e. mitigation of the inhibitory matrix of the glial scar with chondroitinase; transplantation of a PNG into an SCI cavity; chondroitinase digestion of plasticity-limiting perineuronal nets). After the completion of these experiments, we will have identified novel therapeutic avenues to foster functional repair after SCI.

项目摘要成熟的中枢神经系统受伤后缺乏成功再生是由于内在和环境障碍。尽管已经在现场取得了进展，但克服了这些障碍强大的功能轴突再生和恢复仍然是一个重大挑战。我们以初步数据为基础并假设损伤后复发的无与伦比介导的神经元激活是一种增强的手段功能轴突再生。此外，我们将测试神经元激活增加轴突的假设通过MTOR激活和增加动态微管的再生。我们将这些假设都体外使用成年背根神经神经元培养和体内使用背根碎片，背柱的体内脊髓损伤（SCI）/外周神经移植（PNG）和不完整的宫颈SCI/PNG模型。在AIM 1中，我们将阐明重复的化学神经元激活如何增强轴突再生。在AIM 2中，我们将评估神经元激活是单独的还是与增加动态微管的操作结合和mTOR激活 - 促进功能性轴突再生。我们将集体：1）阐明机制神经元激活如何增强生长的背后，有可能识别新的治疗靶标； 2）确定神经元激活在不同损伤模型中增强再生的程度（背根碎，SCI）； 3）确定神经元激活在不同群体的神经元中是否具有不同的作用（DRG VS。 CNS）; 4）测试是否使用独特的多方面方法制备有意义的轴突再生那就是：a）使用化学发生神经元激活 - 与动态微管进一步增加和/或MTOR激活 - 增强轴突生长反应； b）提供了更加验证的损伤后的环境（即用软骨酶缓解神经胶质疤痕的抑制基质；将PNG移植到SCI腔中；软骨蛋白酶消化的限制性限制性周神经元网）。完成这些实验后，我们将确定新的治疗途径以促进功能科学后修复。