Towards a therapy to regenerate corticospinal axons

寻找再生皮质脊髓轴突的疗法

• 批准号: 8318598
• 负责人: OSWALD STEWARD
• 金额: $ 33.57万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318598
• 关键词: Address; Animals; Axon; Biological; Cells; Cerebral cortex; Complement 5a; Corticospinal Tracts; Cues; Development; Dorsal; Genetic; Growth; Handedness; Image; Immunoelectron Microscopy; Injury; Intervention; Lesion; Mediating; Methods; Modeling; Molecular; Molecular Target; Motor; Mus; Natural regeneration; Nature; Neurons; Outcome; Paralysed; Pathway interactions; Pattern; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Procedures; Protein Biosynthesis; Proteins; Recovery; Recovery of Function; Research; Residual state; Ribosomal Protein S6; Specificity; Spinal; Spinal Cord Lesions; Spinal cord injury; Synapses; Testing; Therapeutic; Time; Tissues; axon regeneration; base; cell growth; improved; inhibitor/antagonist; innovation; mTOR protein; mouse model; non-genetic; novel; postsynaptic; pre-clinical; regenerative; regenerative therapy; research study; response; restoration; tensin

DESCRIPTION (provided by applicant): This project is dedicated to discovering ways to induce regeneration of the corticospinal tract (CST) and recovery of motor function after spinal cord injury (SCI). The CST is the pathway that is responsible for the ability to move voluntarily. Damage to the CST as a result of a spinal cord injury is the reason people are paralyzed. The present project is based on recent extraordinary discoveries that the CST can be induced to regenerate following spinal cord injury by targeting molecular pathways that control cell growth in development, specifically phosphatase and tensin inhibitor (PTEN). PTEN is responsible for shutting down the type of protein synthesis that is critical for cell growth during development. PTEN acts by blocking the mammalian target of rapamycin, (mTOR), so deletion of PTEN releases inhibition on mTOR, which in turn allows the cell to synthesize proteins that are critical for cell growth. Importantly, the same molecular pathways are also the key to allowing neurons to regenerate their axons following injury. Based on this, recent studies have shown that genetic deletion of PTEN in mice allows neurons to mount a robust regenerative response. Most critically, our studies demonstrate that when PTEN is deleted in neurons in the cerebral cortex, the neurons that give rise to the CST are able to robustly regenerate their axons after SCI. The fact that regeneration of the CST can be successfully induced provides us with an unprecedented opportunity to address a question that is central to regeneration research-whether it is possible to induce regeneration in a therapeutically-relevant time frame and whether inducing CST regeneration is enough to restore circuits of sufficient specificity to allow some degree of restoration of motor function. The project uses anatomical and physiological methods to assess the degree to which regenerated axons grow along normal tracts, to normal targets, form functional synapses, and contribute to motor function. Pre-clinical experiments will also assess whether it is possible to down-regulate PTEN in a therapeutically-relevant time frame and using non-genetic interventions.

描述（由申请人提供）：该项目致力于探索诱导皮质脊髓束（CST）再生和脊髓损伤（SCI）后运动功能恢复的方法。 CST 是负责自主移动能力的途径。脊髓损伤导致的 CST 损伤是人们瘫痪的原因。本项目基于最近的非凡发现，即通过靶向控制发育中细胞生长的分子途径，特别是磷酸酶和张力蛋白抑制剂 (PTEN)，可以诱导 CST 在脊髓损伤后再生。 PTEN 负责关闭对发育过程中细胞生长至关重要的蛋白质合成类型。 PTEN 通过阻断哺乳动物雷帕霉素靶点 (mTOR) 发挥作用，因此删除 PTEN 会释放对 mTOR 的抑制，从而使细胞能够合成对细胞生长至关重要的蛋白质。重要的是，相同的分子途径也是神经元在受伤后再生轴突的关键。基于此，最近的研究表明，小鼠中 PTEN 的基因缺失可以使神经元产生强大的再生反应。最重要的是，我们的研究表明，当大脑皮层神经元中的 PTEN 被删除时，产生 CST 的神经元能够在 SCI 后稳健地再生其轴突。可以成功诱导 CST 再生的事实为我们提供了前所未有的机会来解决再生研究的核心问题——是否有可能在治疗相关的时间范围内诱导再生，以及诱导 CST 再生是否足以恢复足够特异性的电路，以允许一定程度的运动功能恢复。该项目使用解剖学和生理学方法来评估再生轴突沿着正常束生长、到达正常目标、形成功能性突触以及对运动功能的贡献程度。临床前实验还将评估是否有可能在治疗相关的时间范围内并使用非遗传干预措施下调 PTEN。