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，轴突缺失，脱髓鞘，以及严重的是，脊髓的能力有限 神经元再生。与挫伤患者相比，穿透性SCI患者 由于可塑性而恢复一些功能，并且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，他们受到环境的限制，其中包含的因素供应不足， 促进再生，并提供充足的抑制再生的因子。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）通过抑制性环境驱动轴突生长，从而能够促进和引导 轴突生长进入、穿过并重新进入备用宿主组织，与完整的宿主组织形成功能性连接。 伤口下方的电路我们已经证明，桥结构导致与宿主组织的整合， 减少二次损伤，防止囊肿形成。桥的通道支撑着强健的轴突 长入并穿过皮质脊髓束（CST）轴突的桥，并通过 植入后10周。桥植入本身促进了功能恢复， 表达抗炎因子的桥梁通过减少继发性炎症反应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相关的基因组成， 修复.该提案建立在这些结果的基础上，并通过提供 穿通伤合并生物材料桥接后急性抗炎因子的变化 点我们假设，急性递送因子以减轻炎症将使抑制分子最小化 和备用再生能力轴突邻近损伤，这种方法的组合， 延迟的桥植入和药物微管稳定将驱动定向轴突再生 通过通道重新进入尾侧实质，并与慢性SCI中的完整电路形成突触。 为了实现这一目标，基因递送将用于调节炎症和减少抑制性分子 在损伤的急性期表达（目的1）。再生在慢性时间进行了调查，使用桥梁 与微管稳定剂埃博霉素B（EpoB）联合，通过损伤驱动轴突生长 与完整的电路连接（目标2）。在Aim中研究了急性和慢性治疗的组合 3.桥平台可以支持再生过程的多个方面，并且定义良好的 已经在临床中使用的组件可以促进最终转化为临床。这些 研究提供了关于早期损伤干预如何影响后期再生的关键信息。

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