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: 10469553
• 负责人: Aileen J Anderson
• 金额: $ 43.55万
• 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/10469553
• 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; neural repair; neurodevelopment; novel; prevent; programs; recruit; regenerative; 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) 会导致损伤水平以下的瘫痪，这是由神经元和神经元引起的 少突胶质细胞死亡、轴突丢失、脱髓鞘，以及最严重的脊髓功能有限 神经元得以再生。与挫伤患者相比，穿透性 SCI 患者不会 由于可塑性而恢复某些功能，并依赖于脊髓通路的重新连接，例如通过 支持真正轴突再生的生物材料桥。尽管脊髓神经元具有先天的 再生能力受到环境的限制，环境因素供给不足 促进再生，并提供大量抑制再生的因子。我们的长期目标是 开发基于生物材料的联合疗法，可以 1) 桥接，2) 调节损伤 微环境，3）通过抑制性环境驱动轴突生长，从而促进和指导 轴突生长进入、穿过并重新进入幸存的宿主组织，与完整的宿主组织形成功能连接 受伤部位下方的电路。我们已经证明桥结构导致与宿主组织的整合， 减少继发性损伤，并防止囊肿形成。桥的通道支持强大的轴突 向内生长并穿过皮质脊髓束 (CST) 轴突的桥，并沿脊髓向下延伸 >2 毫米 植入后10周。桥植入本身可增强功能恢复，并可修改 表达抗炎因子的桥梁通过减少继发性进一步增强功能恢复 损伤并启动由与神经发育和相关基因组成的再生程序 维修。该提案建立在这些结果的基础上，并通过提供以下内容重点关注慢性时间点的再生 穿透性损伤后急性抗炎因子结合长期生物材料桥 点。我们假设急性递送因子以减少炎症将最大限度地减少抑制分子 和损伤附近备用的具有再生能力的轴突，并且这种方法与 延迟桥植入和药物微管稳定将推动定向轴突再生 在慢性 SCI 中，通过通道重新进入尾部实质和突触到完整的电路上。 为了实现这一目标，基因递送将用于调节炎症并减少抑制分子 损伤急性期的表达（目标 1）。使用桥研究长期再生 与微管稳定剂埃博霉素 B (EpoB) 结合使用，通过损伤驱动轴突生长 连接完整的电路（目标 2）。 Aim 研究了急性和慢性疗法的结合 3. 桥梁平台可以支持再生过程的多个方面，并且定义明确 已在临床中使用的组件可能有助于最终转化为临床。这些 研究提供了关于早期损伤干预如何影响以后再生的关键信息。