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：
10553085
负责人：
Veronica Jean Tom
金额：
$ 33.14万
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/10553085
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.

项目概要成熟的中枢神经系统损伤后缺乏成功的再生是由于内在的和尽管该领域已经取得了进展，但要克服这些障碍才能实现目标。强大的功能性轴突再生和恢复仍然是一个重大挑战。并发现受伤后反复出现的 DREADD 介导的神经激活是增强此外，我们将检验神经激活增加轴突的假设。我们将通过 mTOR 激活和增加动态微管来实现再生。体外使用成人背根神经节神经元培养物，体内使用背根压碎、背柱脊髓损伤 (SCI)/周围神经移植 (PNG) 和不完整颈椎 SCI/PNG 模型在目标 1 中，我们。将阐明重复的化学遗传学神经激活如何增强轴突再生。评估神经激活是否单独或与增加动态微管的操作相结合和 mTOR 激活——促进功能性轴突再生。我们将共同：1) 阐明机制。神经激活如何促进生长，潜在地确定新的治疗靶点；2) 确定不同损伤模型（背根挤压，SCI）中神经激活增强再生的程度； 3）确定神经激活在不同的神经元群体中是否具有不同或相似的效果（DRG与DRG） CNS）；4）测试是否使用独特的多方面方法促进有意义的轴突再生 a) 使用化学遗传学神经激活——可能同时进一步增加动态微管和/或 mTOR 激活 – 增强轴突生长反应 b) 提供更适宜的生长；受伤后的环境（即用软骨素酶减轻神经胶质疤痕的抑制基质；将 PNG 移植到 SCI 腔中；软骨素酶消化可塑性限制的神经神经网络）。完成这些实验后，我们将确定新的治疗途径来促进功能性 SCI后修复。