Nonpeptide Neurotrophic Mechanisms in Spinal Cord Repair

项目摘要/摘要 创伤性脊髓损伤(SCI)与感觉和运动功能的缺陷有关，包括完全性 严重者可致瘫痪。严重的脊髓损伤目前是无法治愈的，因为没有药物可以逆转 与损伤相关的神经组织损伤。事实上，与可以愈合和恢复功能的外周组织不同 在撕裂伤和挫伤后，脊髓对再生或置换的抵抗力是出了名的。 损伤后与大脑的神经连接。这项研究的总体目标是增加对 研究神经再生机制，发现治疗脊髓损伤的新的药理靶点。 动物模型实验表明，增强脊髓中神经生长因子的生物活性 脐带可以将组织推向再生程序。我们已经制定了一项战略，可以提供 使用合成的小分子化合物来促进这种作用。在合理选择和筛选几个 小分子化合物，我们发现了几个成员可以有效地促进受损神经的再生 组织培养模型中的细胞。其中一些化合物正被用作其他药物的批准药物 所有六种化合物都能从血液进入中枢神经系统。共享的 化合物的生化性质，允许开发一个统一的假说，将 这些非肽类神经营养化合物对生长因子信号通路和再生的影响。 我们认为，合乎逻辑的下一步是澄清这些化合物的作用机制。完成 这一项目中提议的实验将产生应该促进这种理解的结果。 此后，我们将利用所获得的知识，开始重新调整现有药物的用途或 设计新的化合物，促进神经细胞再生，修复受损的神经连接 治疗脊髓损伤患者。

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.