Wild-type nerve grafting promotes reinnervation of SOD1 muscle

野生型神经移植促进 SOD1 肌肉的神经支配

• 批准号: 8512110
• 负责人: Martin J Pinter
• 金额: $ 23.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512110
• 关键词: Adult; Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Appearance; Attention; Axon; Back; Behavior; Cell Death; Cells; Cessation of life; Data; Denervation; Development; Disease; Disease Progression; Distal; Environment; Enzymes; Event; Fibroblasts; Goals; Human; Inherited; Learning; Long-Term Effects; Modeling; Motor; Motor Neuron Disease; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle denervation procedure; Mutate; Mutation; Natural regeneration; Necrosis; Nerve; Neuroglia; Neuromuscular Junction; Neurons; Performance; Peripheral Nerves; Play; Postoperative Period; Presynaptic Terminals; Process; Research; Role; Schwann Cells; Testing; Time; Tissue Grafts; Toxic effect; Transgenic Mice; Work; base; cell type; experience; gain of function; improved; innovation; interest; killings; motor neuron degeneration; mouse model; mutant; nerve supply; neuron loss; overexpression; prevent; protein expression; public health relevance; reinnervation; theories; time interval

DESCRIPTION (provided by applicant): Motor neuron (MN) degeneration commences at the neuromuscular junction (NMJ) in the SOD1 model of motor neuron disease (MND). The NMJ features 3 cell types present in close physical proximity: neuronal (motor terminal), terminal Schwann cell (TSC), and muscle fiber. In preliminary work, we found that TSCs and pre-terminal Schwann cells (SCs) in SOD1 mice rapidly disappear from denervated NMJs whereas wildtype (WT) TSCs remain at denervated NMJs and help guide reinnervation. This SOD1 abnormality can be expected to hinder or prevent reinnervation of denervated muscle fibers by surviving MNs and accelerate the development of weakness. We considered the possibility that SOD1 endplates vacated by SOD1 TSCs can be reoccupied by wildtype SCs. To test this, we used a syngeneic approach and grafted pre-degenerated WT peripheral nerves into SOD1 muscles that were experimentally denervated at the same time. Preliminary evidence shows that after 2 weeks, muscle reinnervation is more rapid and robust in the presence of grafts and resembles reinnervation in WT animals. Moreover, this innervation persists at longer, post-grafting intervals. In Aim 1, we will extend the characterization of these long term effects and learn whether they are associated with reduced MN cell death and improved muscle and motor unit performance. In addition, we will determine whether WT grafts can improve or preserve muscle innervation during the natural disease course. In Aim 2, we will graft primary cultured WT SC, fibroblasts (FB) and acellular WT nerves and learn which of these major graft components is responsible for WT nerve graft effects in denervated SOD1 muscle. Finally, the appearance of TSCs and distal SCs in SOD1 muscles soon after denervation suggests that cell death may be involved in their disappearance. In Aim 3, we will use immunolabels for necrosis and apoptosis to learn whether SOD1 SCs experience cell death soon after denervation in order to gain clues about possible trigger mechanisms. We hope that this innovative use of grafting tissue/cells will produce new clues about possible therapies and extend understanding about how SCs contribute to MND in SOD1 mice.

描述（由申请人提供）：运动神经元疾病（MND）的SOD1模型中，运动神经元（MN）退行性变始于神经肌肉连接处（NMJ）。NMJ有3种细胞类型，它们在物理上接近：神经元（运动端）、终末雪旺细胞（TSC）和肌纤维。在前期工作中，我们发现SOD1小鼠的TSCs和前终末雪旺细胞（SCs）迅速从失神经NMJs中消失，而野生型（WT） TSCs则保留在失神经NMJs中，并有助于指导神经再生。这种SOD1异常可能会阻碍或阻止存活的MNs对失神经支配肌纤维的再神经支配，并加速无力的发展。我们认为SOD1 TSCs空出的SOD1终板可能被野生型sc重新占用。为了验证这一点，我们采用了同系方法，将退化前的WT周围神经移植到SOD1肌肉中，SOD1肌肉同时被实验性地去神经化。初步证据表明，2周后，在移植物的存在下，肌肉神经再生更加迅速和强健，与WT动物的神经再生相似。此外，这种神经支配在移植后持续时间更长。在Aim 1中，我们将扩展这些长期影响的特征，并了解它们是否与减少MN细胞死亡和改善肌肉和运动单元性能有关。此外，我们将确定WT移植物是否可以改善或保留自然疾病过程中的肌肉神经支配。在Aim 2中，我们将移植原代培养的WT SC、成纤维细胞（FB）和脱细胞WT神经，并了解这些主要移植物成分中哪一种对去神经SOD1肌肉的WT神经移植物作用负责。最后，在去神经支配后不久，SOD1肌肉中出现了TSCs和远端SCs，这表明细胞死亡可能参与了它们的消失。在Aim 3中，我们将使用坏死和凋亡的免疫标记来了解SOD1 SCs在去神经支配后是否很快经历细胞死亡，以获得可能的触发机制的线索。我们希望这种移植组织/细胞的创新应用将为可能的治疗方法提供新的线索，并扩展对sc如何促进SOD1小鼠MND的理解。