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: 10700124
• 负责人: Aileen J Anderson
• 金额: $ 43.76万
• 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/10700124
• 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; Growth; 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; Penetration; Pharmacologic Substance; 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; behavior test; combinatorial; functional restoration; gene therapy; immunoregulation; implantation; innovation; myelination; neural repair; neurodevelopment; novel; pharmacologic; 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)导致损伤水平以下的瘫痪，这是由神经元和 少突胶质细胞死亡、轴突丢失、脱髓鞘，更严重的是，脊髓的能力有限 神经元需要再生。与挫伤患者相比，穿透性脊髓损伤患者不会 由于可塑性而恢复一些功能，并依赖于脊柱通路的重新连接，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 再生的能力，它们受到环境的限制，环境包含的因素供应不足，无法 促进再生，并提供充足的抑制再生的因素。我们的长期目标是 开发一种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)通过抑制环境推动轴突生长，从而促进和引导 轴突生长到、穿过和重新进入备用的宿主组织，形成与完整的 伤处下方的电路。我们已经证明了桥结构导致与宿主组织的整合， 减少二次伤害，防止囊肿形成。桥的通道支撑着健壮的轴突 长入并穿过皮质脊髓束(CST)轴突的桥，沿脊髓向下延伸2 mm 植入后10周。桥接植入本身增强了功能恢复，并修改了 表达抗炎因子的桥通过减少继发性炎症进一步增强功能恢复 损伤并启动再生程序，该程序由与神经发育和 修理。该提案以这些结果为基础，重点关注慢性时间点的再生，通过提供 生物材料桥复合穿透性损伤后急性抗炎因子的变化 积分。我们假设，急性释放抑制炎症的因子将使抑制分子最小化。 和邻近损伤的备用再生能力轴突，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 在慢性脊髓损伤中，通过这些通道重新进入尾侧实质并突触到完整的回路上。 为了达到这个目标，基因传递将被用来调节炎症和减少抑制分子 损伤急性期的表达(目标1)。利用桥梁研究慢性再生。 与微管稳定剂EpoB(EpoB)相结合，通过损伤驱动轴突生长 连接完整的电路(AIMS 2)。急性和慢性疗法的结合在AIM中进行了研究 3.桥接平台可以支持多方面的再生过程，并且定义良好 已经在临床上使用的组件可能会促进最终转化到临床上。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。

项目成果

An injectable PEG hydrogel controlling neurotrophin-3 release by affinity peptides.

• DOI: 10.1016/j.jconrel.2020.12.045
• 发表时间: 2021-02-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Wang J;Youngblood R;Cassinotti L;Skoumal M;Corfas G;Shea L
• 通讯作者: Shea L