Towards a therapy to regenerate corticospinal axons

描述（由申请人提供）：本项目致力于发现诱导皮质脊髓束（CST）再生和脊髓损伤（SCI）后运动功能恢复的方法。CST是负责自愿移动能力的途径。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通过阻断雷帕霉素的哺乳动物靶点（mTOR）发挥作用，因此PTEN的缺失释放了对mTOR的抑制，从而允许细胞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允许神经元在损伤后再生轴突的关键。基于此，最近的研究表明，小鼠中PTEN的基因缺失允许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被删除时，引起CST的神经元能够在SCI后稳健地再生其轴突。事实上，再生的CST可以成功地诱导为我们提供了一个前所未有的机会，以解决一个问题，这是中央再生研究是否有可能诱导再生的治疗相关的时间框架，以及是否诱导CST再生是足以恢复电路的足够的特异性，允许一定程度的恢复运动功能。该项目使用解剖学和生理学方法来评估再生轴突沿沿着正常神经束生长到正常靶点、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范围内和使用非遗传干预下调PTEN。 公共卫生相关性：该项目建立在新发现的基础上，即轴突再生可以通过靶向发育过程中控制细胞生长的分子途径在脊髓损伤后诱导。该项目将评估是否有可能在治疗相关的时间范围内靶向这些分子途径，以及再生是否足以恢复运动功能。

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. PUBLIC HEALTH RELEVANCE: This project builds upon the novel discovery that axon regeneration can be induced following spinal cord injury by targeting molecular pathways that control cell growth during development. The project will assess whether it is possible to target these molecular pathways in a therapeutically relevant time frame and whether the regeneration is sufficient to restore motor function.