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)不可逆转地损害CST，导致自主运动丧失 受伤以下的控制，包括手功能，这对独立的日常生活至关重要 四肢瘫痪。最近，我们在实现CST再生方面取得了很大进展 脊髓损伤后使用脊髓神经干细胞或祖细胞移植。然而，一个预期的和 最近从我们的RR&D资助的研究中发现的重要发现：只有后肢CST轴突 再生为植入颈部脊髓损伤部位的移植物；前肢CST轴突很少再生。 这些发现提出了一种假设，即加强前肢CST轴突的再生将 当结合神经干细胞移植时，显著改善脊髓损伤后的功能结果。 在这笔补助金的续期过程中，我们建议阐明穷人背后的机制 前肢CST的再生能力及提高再生能力的实验方法 我们假设前肢CST再生将进一步促进前肢功能恢复 在SCI之后。具体目标1：使用RNA测序来确定相关的分子机制 大鼠前肢CST轴突再生与后肢CST轴突再生的差异。理解 前肢CST不能再生的机制对我们的设计很重要 促进前肢CST再生的试验。具体目标2：确定是否 短暂阻断前肢CST突触活性可使前肢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化，而后肢 但CST并非如此。我们假设这些广泛的侧支和它们的突触连接 前肢CST的存在限制了它们的再生。最近的研究支持这一假设，因为删除了 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：探讨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RR&D的前一段时间 我们发现PTEN/SOCS3条件性缺失显著增加了整体CST 脊髓损伤后再生为干细胞移植，但我们没有分别标记前肢和 后肢CST轴突。我们将确定PTEN/SOCS3基因缺失或抑制 通过反义寡核苷酸治疗特异性地促进前肢CST作为一种 替代机制。 所有建议的研究均有初步可行性数据支持，并可由 Pi和他的合作者在SCI研究领域具有丰富的经验。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，并确定开发人类脊髓损伤治疗方法的前进道路。