Multi-channeled Bridges for Promoting Chronic Spinal Cord Repair

促进慢性脊髓修复的多通道桥

• 批准号: 10249977
• 负责人: Aileen J Anderson
• 金额: $ 44.64万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10249977
• 关键词: Acute; Anti-Inflammatory Agents; Architecture; Attenuated; Axon; Behavioral Assay; Biocompatible Materials; Cell Death; Cervical spinal cord injury; Chronic; Clinic; Combined Modality Therapy; Complex; Contusions; Corticospinal Tracts; Cyst; Defect; Demyelinations; Environment; Epothilone B; Gene Delivery; Genes; Geometry; Goals; Implant; In Situ; Individual; Inflammation; Inflammatory Response; Injury; Interleukin-10; Interleukin-10 Overexpression; Interleukin-4; Intervention; Lentivirus; Lesion; Leukocytes; Locomotor Recovery; Measures; Mediating; Microtubule Stabilization; Microtubules; Modeling; Modification; Motor; Natural regeneration; Neurons; Oligodendroglia; Paralysed; Patients; Pharmacologic Substance; Pharmacology; Process; Recovery; Recovery of Function; Research; Site; Spinal Cord; Spinal cord injury; Structure; Synapses; Testing; Therapeutic; Therapeutic Intervention; Thoracic Injuries; Time; Tissues; Translations; Tube; axon growth; axon regeneration; base; behavior test; combinatorial; functional restoration; gene therapy; immunoregulation; implantation; innovation; myelination; neurodevelopment; novel; prevent; programs; recruit; regenerative; repaired; restoration; safe patient; spinal cord repair; spinal pathway; synaptogenesis

Spinal Cord Injury (SCI) causes paralysis below the level of damage, which results from neuron and oligodendrocyte cell death, axonal loss, demyelination, and critically, the limited capacity of spinal cord neurons to regenerate. In contrast to patients with contusion injuries, individuals with penetrating SCI do not recover some function due to plasticity and are reliant on reconnection of spinal pathways, such as through biomaterial bridge that support true axonal regeneration. Although spinal cord neurons have the innate capacity to regenerate, they are limited by the environment, which contains an insufficient supply of factors to promote regeneration, and an abundant supply of factors that inhibit regeneration. Our long-term goal is to develop a combination therapy based on biomaterials that can 1) bridge, 2) modulate the injury microenvironment, 3) drive axon growth through an inhibitory milieu enabling the promotion and direction of axonal growth into, through, and re-entering spared host tissue to form functional connections with intact circuitry below the injury. We have shown that the bridge architecture leads to integration with the host tissue, reduces secondary injury, and prevents cyst formation. The channels of the bridge support robust axonal ingrowth into and through the bridge for corticospinal tract (CST) axons and extend >2 mm down the cord by 10 weeks post-implantation. Bridge implantation enhances functional recovery by itself, and modification of the bridge to express anti-inflammatory factors further enhances function recovery by decreasing the secondary damage and initiating a regenerative program that consists of genes associated with neural development and repair. This proposal builds on these results and focuses on regeneration at chronic time points by providing anti-inflammatory factors acutely after a penetrating injury combined with a biomaterial bridge at a chronic time points. We hypothesize that acute delivery of factors to reduce inflammation will minimize inhibitory molecules and spare regeneration competent axons adjacent to the injury, and that combination of this approach with delayed bridge implantation and pharmaceutical microtubule stabilization will drive directed axon regrowth through the channels to re-enter the caudal parenchyma and synapse onto intact circuitry in chronic SCI. Toward this goal, gene delivery will be used to modulate inflammation and reduce inhibitory molecule expression during the acute stage of injury (Aim 1). Regeneration at chronic times is investigated using bridges in combination with the microtubule stabilizer epothilone B (EpoB), which drives axon growth through the injury to connect with intact circuitry (Aims 2). The combination of acute and chronic therapies is investigated in Aim 3. The bridge platform can support multiple aspects of the regenerative process, and the well-defined components, which have been used in the clinic, may facilitate the ultimate translation to the clinic. These studies provide critical information on how early injury interventions can impact regeneration at later times.

脊髓损伤（SCI）导致瘫痪水平低于损伤水平，这是由神经元和 少突胶质细胞死亡，轴突丧失，脱髓鞘和批判性的脊髓能力有限 神经元再生。与挫伤损伤的患者相反，穿透SCI的个体不 恢复由于可塑性而恢复一些功能，并依赖于重新连接脊柱途径，例如通过 支持真正的轴突再生的生物材料桥。虽然脊髓神经元具有先天 再生能力，它们受环境的限制，环境不足以供应因素 促进再生，并大量抑制再生的因素。我们的长期目标是 基于生物材料的结合疗法，可以桥接1）2）调节伤害 微环境，3）驱动轴突的生长通过抑制环境，以促进和方向 轴突生长进入，通过和重新进入遗憾的宿主组织，形成完整的功能连接 受伤以下的电路。我们已经表明，桥梁结构导致与宿主组织的集成 减少次要损伤并防止囊肿形成。桥梁的通道支持强大的轴突 向内伸入并穿过皮质脊髓束（CST）轴突，然后向下延伸> 2 mm 植入后10周。桥梁植入本身可以增强功能恢复，并修改 表达抗炎因子的桥梁通过减少次级进一步增强功能恢复 损害和启动再生程序，该程序由与神经发育相关的基因组成 维修。该建议以这些结果为基础，并通过提供 穿透性损伤后，抗炎因子在慢性时与生物材料桥结合 点。我们假设急性递送因素减少炎症会最大程度地减少抑制性分子 和备用再生能干的轴突与受伤相邻，这种方法的结合与 延迟的桥梁植入和药物微管稳定将驱动轴突再生 通过通道重新进入尾部实质并突触到慢性SCI中的完整电路。 为了实现这一目标，基因输送将用于调节炎症并减少抑制分子 在受伤的急性阶段表达（AIM 1）。使用桥梁研究了慢性时代的再生 与微管稳定剂Epothilone B（EPOB）结合，通过损伤驱动轴突生长 与完整的电路连接（目标2）。 AIM研究了急性和慢性疗法的结合 3。桥平台可以支持再生过程的多个方面，并且定义明确 在诊所中使用的组件可能有助于最终转化为诊所。这些 研究提供了有关早期损伤干预措施在以后如何影响再生的关键信息。