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.

项目描述（申请人提供）：本项目致力于探索脊髓损伤（SCI）后诱导皮质脊髓束（CST）再生和运动功能恢复的方法。CST是负责自主移动能力的通道。脊髓损伤导致的CST损伤是人们瘫痪的原因。目前的项目是基于最近的非凡发现，通过靶向控制细胞生长发育的分子途径，特别是磷酸酶和紧张素抑制剂（PTEN），可以诱导脊髓损伤后的CST再生。PTEN负责关闭在发育过程中对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蛋白（mTOR）而起作用，因此PTEN的缺失释放了对mTOR的抑制，这反过来又允许细胞合成对细胞生长至关重要的蛋白质。重要的是，同样的分子通路也是神经元损伤后轴突再生的关键。基于此，最近的研究表明，小鼠PTEN基因缺失可以使神经元产生强大的再生反应。最关键的是，我们的研究表明，当大脑皮层神经元中的PTEN缺失时，产生CST的神经元能够在脊髓损伤后强健地再生其轴突。CST的再生可以成功诱导，这一事实为我们提供了一个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框架内诱导再生，以及诱导CST再生是否足以恢复足够特异性的电路，从而在一定程度上恢复运动功能。该项目使用解剖学和生理学方法来评估再生轴突沿正常束生长到正常靶点、形成功能性突触和促进运动功能的程度。临床前实验还将评估是否有可能在治疗相关的时间框架内使用非遗传干预手段下调PTEN。