Nonpeptide Neurotrophic Mechanisms in Spinal Cord Repair

项目总结/摘要 创伤性脊髓损伤（SCI）与感觉和运动功能缺陷相关，包括完全性脊髓损伤。 严重者瘫痪。严重的SCI目前是无法治愈的，因为没有药物可以逆转 损伤相关的神经组织损伤。事实上，与可以愈合并恢复功能的外周组织不同， 在撕裂伤和挫伤之后，脊髓对再生或替换有很强的抵抗力 大脑的神经连接。这项研究的总体目标是增加对 研究神经再生机制，并发现治疗SCI的新药理学靶点。 在动物模型中的实验表明，增强脊髓中神经生长因子的生物活性， 脐带可以推动组织走向再生程序。我们制定了一项战略， 这种增强使用合成小分子化合物。经过合理的选择和筛选， 小分子化合物，我们发现了几个成员，以有力地促进受损神经的再生 组织培养模型中的细胞。其中一些化合物被用作其他药物的批准药物。 所有六种化合物都能够从血流进入CNS。共享 这些化合物的生化特性允许发展一个统一的假设，将以下作用联系起来 这些非肽类神经营养化合物对生长因子信号传导途径和再生效应的影响。 我们认为，合乎逻辑的下一步是澄清这些化合物的工作机制。完成 该项目中提出的实验将产生促进这种理解的结果。 此后，我们将利用所获得的知识，开始重新利用现有的药物， 设计新的化合物，促进神经细胞再生和修复受损的神经连接， 治疗SCI患者。

Project Summary/Abstract Traumatic spinal cord injury (SCI) is associated with deficits in sensory and motor function, including complete paralysis in severe cases. Severe SCI is currently incurable as there are no medications that can reverse the injury-related nerve tissue damage. Indeed, unlike peripheral tissues that can heal and regain function following lacerations and contusive injuries, the spinal cord is notoriously resistant to regrowth or replacement of neural connections with the brain after injury. The overall goal of this research is to increase understanding of neuroregenerative mechanisms and uncover novel pharmacological targets for the treatment of SCI. Experiments in animal models suggest that boosting the biological activity of nerve growth factors in the spinal cord can nudge the tissue toward a program of regeneration. We have developed a strategy that could deliver such boost using synthetic small molecule compounds. Following rational selection and screening of several small-molecule compounds, we found several members to potently promote the regrowth of damaged nerve cells in a tissue culture model. Some of these compounds are being used as approved drugs for other disorders, and all six compounds are capable of crossing into the CNS from the bloodstream. The shared biochemical properties of the compounds allowed to develop a unifying hypothesis that links the actions of these nonpeptide neurotrophic compounds to the pathways of growth factor signaling and regenerative effects. We believe that the logical next step is to clarify the mechanism by which these compounds work. Completion of the experiments proposed in this project will generate results that should advance such understanding. Thereafter, we will use the knowledge gained to begin to work toward repurposing existing medications or designing new compounds that would promote nerve cell regrowth and repair damaged nerve connections to treat SCI patients.