Enhancing Forelimb Recovery by Promoting Forelimb Corticospinal Tract Regeneration after Spinal Cord Injury

通过促进脊髓损伤后前肢皮质脊髓束再生来增强前肢恢复

• 批准号: 10533107
• 负责人: Pengzhe Lu
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10533107
• 关键词: American; Antisense Oligonucleotide Therapy; Automobile Driving; Axon; Bilateral; Brain; CISH gene; Caring; Cells; Central Nervous System; Cervical; Cervical spinal cord injury; Clinical; Contusions; Corticospinal Tracts; Data; Distal; Embryo; Experimental Designs; Feeling; Forelimb; Funding; Gene Expression Profile; Genes; Genetic; Grant; Grant Review; Growth; Hand functions; Hindlimb; Human; Injury; Knowledge; Label; Life; Mission; Modeling; Molecular; Motor; Mus; Natural regeneration; Nerve Regeneration; Neurons; Nonpenetrating Wounds; PTEN gene; Paralysed; Patient Care; Quadriplegia; Rattus; Recovery; Recovery Support; Recovery of Function; Regenerative capacity; Rehabilitation therapy; Research; Signal Transduction; Site; Spinal Cord; Spinal cord injury; Synapses; System; Testing; Training; Tumor Suppressor Genes; Veterans; Viral; Work; axon growth; axon regeneration; clinically relevant; combinatorial; designer receptors exclusively activated by designer drugs; experience; functional improvement; improved; injured; knock-down; loss of function; motor control; nerve stem cell; neural network; prevent; regenerative; response to injury; skills; small hairpin RNA; stem cells; success; transcriptome sequencing; transmission process

The corticospinal tract (CST) is the most important voluntary motor control system in humans. Spinal cord injury (SCI) irreversibly damages the CST, which leads to loss of voluntary motor control below the injury, including hand function that is critical for independent daily life for quadriplegia. Recently we have made great progress in achieving substantial CST regeneration after SCI using spinal cord neural stem cell or progenitor cell grafts. However, an expected and important finding recently emerged from our RR&D-funded studies: only hindlimb CST axons regenerate into grafts placed into sites of cervical SCI; forelimb CST axons rarely regenerate. These findings raise the hypothesis that enhancing regeneration of forelimb CST axons will significantly improve functional outcomes after SCI when combined with neural stem cell grafts. In the renewal of this grant, we propose to elucidate mechanisms underlying the poor regenerative capacity of the forelimb CST and to test experimental approaches for enhancing forelimb CST regeneration that we hypothesize will further improve forelimb functional recovery after SCI. Specific Aim 1: Use RNA Sequencing to identify molecular mechanisms associated with differences in forelimb-CST and hindlimb-CST axonal regeneration in rats. Understanding mechanisms why forelimb CST does not regenerate is important to help us designing experiments to enhance forelimb CST regeneration. Specific Aim 2: Determine whether transient blockade of forelimb CST synaptic activity enables forelimb CST regeneration. Our recently study showed that forelimb CST axon is highly collateralized in the brain, but hindlimb CST does not. We hypothesize that these extensive collaterals and their synaptic connections of forelimb CST limit their regeneration. Recent studies support this hypothesis since deletion or suppression of Cacna2d2 gene that involve in synaptic activity promotes axon regeneration. Specific Aim 3: Explore whether PTEN/SOCS3 deletion or suppression will increase forelimb CST regeneration and skilled forelimb function recovery. In the previous period of this RR&D grant we found that PTEN/SOCS3 conditional deletion significantly increased overall CST regeneration into a stem cell graft after SCI, but we did not separately label forelimb and hindlimb CST axons. We will determine whether PTEN/SOCS3 genetic deletion or suppression by antisense oligonucleotide therapy specifically enhances forelimb CST regeneration as an alternative mechanism. All studies proposed are supported by preliminary feasibility data and can be conducted by the PI and his collaborators who have extensive experience in SCI research field. Positive findings of this work will substantially enhance our knowledge of central nervous system regeneration mechanisms, and identify paths forward to developing treatments for human SCI.

皮质脊髓束（CST）是人类最重要的自主运动控制系统。 脊髓损伤 (SCI) 会不可逆地损害 CST，导致自主运动丧失 损伤以下的控制，包括对独立日常生活至关重要的手部功能 四肢瘫痪。最近，我们在实现 CST 大幅再生方面取得了巨大进展 SCI 后使用脊髓神经干细胞或祖细胞移植物。然而，预期和 我们 RR&D 资助的研究最近出现了重要发现：仅后肢 CST 轴突 再生为植入颈椎 SCI 部位的移植物；前肢 CST 轴突很少再生。 这些发现提出了这样的假设：增强前肢 CST 轴突的再生将 与神经干细胞移植相结合可显着改善 SCI 后的功能结果。 在更新这笔赠款时，我们建议阐明贫困人口背后的机制 前肢 CST 的再生能力并测试增强的实验方法 我们假设前肢 CST 再生将进一步改善前肢功能恢复 SCI之后。具体目标 1：使用 RNA 测序来识别相关的分子机制 大鼠前肢 CST 和后肢 CST 轴突再生存在差异。理解 前肢 CST 不再生的机制对于帮助我们设计很重要 增强前肢 CST 再生的实验。具体目标 2：确定是否 前肢 CST 突触活动的短暂阻断使前肢 CST 再生。我们的 最近的研究表明，前肢 CST 轴突在大脑中高度侧支，但后肢 CST 没有。我们假设这些广泛的侧支及其突触连接 前肢 CST 的减少限制了它们的再生。删除后最近的研究支持了这一假设 或抑制参与突触活动的Cacna2d2基因可促进轴突再生。 具体目标 3：探索 PTEN/SOCS3 缺失或抑制是否会增加前肢 CST 再生和熟练的前肢功能恢复。在本次研发前期 我们发现 PTEN/SOCS3 条件删除显着提高了总体 CST SCI后再生为干细胞移植物，但我们没有单独标记前肢和 后肢 CST 轴突。我们将确定PTEN/SOCS3基因是否缺失或抑制 通过反义寡核苷酸疗法特异性增强前肢 CST 再生 替代机制。 所有提议的研究都有初步可行性数据的支持，并且可以由 PI及其合作者在SCI研究领域拥有丰富的经验。积极的发现 这项工作将大大增强我们对中枢神经系统再生的了解 机制，并确定开发人类 SCI 治疗方法的路径。