Towards a therapy to regenerate corticospinal axons

描述(由申请人提供)：该项目致力于探索在脊髓损伤(SCI)后诱导皮质脊髓束(CST)再生和运动功能恢复的方法。CST是负责自主活动能力的通路。脊髓损伤对CST的损害是人们瘫痪的原因。本项目基于最近的非凡发现，即通过靶向控制发育过程中细胞生长的分子途径，特别是磷酸酶和张力蛋白抑制物(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通过阻断哺乳动物的雷帕霉素靶标(MTOR)发挥作用，因此PTEN的缺失释放了对mTOR的抑制，进而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，在小鼠中PTEN的基因缺失使神经元能够启动强大的再生反应。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，产生CST的神经元能够在脊髓损伤后强劲地再生轴突。成功地诱导CST再生的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--是否有可能在与治疗相关的时间框架内诱导再生，以及诱导CST再生是否足以恢复具有足够特异性的回路，以允许某种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轴突生长到正常靶点的程度，形成功能性突触，并对运动功能做出贡献。临床前实验还将评估是否有可能在与治疗相关的时间框架内使用非遗传干预下调PTEN。 公共卫生相关性：该项目建立在一项新发现的基础上，即脊髓损伤后可以通过靶向控制发育过程中细胞生长的分子途径来诱导轴突再生。该项目将评估是否有可能在治疗相关的时间框架内针对这些分子通路，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.