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

• 批准号: 10526142
• 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
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526142
• 关键词: Adult; Affect; American; Cervical spinal cord injury; Chondroitinases; Cicatrix; Data; Digestion; Environment; FRAP1 gene; Fostering; Growth; In Vitro; Injury; Mediating; Microtubules; Modeling; Natural regeneration; Neuraxis; Neurons; Peripheral Nerves; Peripheral nerve injury; Population; Public Health; Recovery; Recurrence; Spinal Cord; Spinal Ganglia; Spinal cord injury; Testing; Transplantation; axon growth; axon regeneration; designer receptors exclusively activated by designer drugs; dorsal column; experimental study; in vivo; new therapeutic target; novel therapeutics; repaired; response; spinal nerve posterior root; therapeutic target

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 环境障碍。尽管该领域已经取得了进展，但克服这些障碍 强大的功能性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 DREADD 介导的神经元反复激活是增强 功能性轴突再生。此外，我们将检验神经元激活增加轴突的假设 通过 mTOR 激活和增加动态微管进行再生。我们将这些我们的假设 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）和不完整的颈椎 SCI/PNG 模型。在目标 1 中，我们 将阐明重复的化学遗传学神经元激活如何增强轴突再生。在目标 2 中，我们将 评估神经元激活是否单独或与增加动态微管的操作相结合 mTOR 激活 – 促进功能性轴突再生。总的来说，我们将：1）阐明机制 神经元激活如何促进生长，有可能确定新的治疗靶点； 2）确定 不同损伤模型（背根挤压，SCI）中神经元激活增强再生的程度； 3）确定神经元激活在不同神经元群体中是否具有不同或相似的影响（DRG与DRG） 中枢神经系统）； 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元激活——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) 提供更有利的增长空间 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 腔内；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。