Nonpeptide Neurotrophic Mechanisms in Spinal Cord Repair

脊髓修复中的非肽神经营养机制

• 批准号: 10613988
• 负责人: ASHIWEL S UNDIEH
• 金额: $ 15.7万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613988
• 关键词: Acceleration; Amitriptyline; Anabolism; Animal Model; Axon; Behavioral; Biochemical; Biological; Biological Assay; Blood Circulation; Brain; Brain-Derived Neurotrophic Factor; Cell Proliferation; Cell Survival; Cell membrane; Cervical; Chemicals; Contusions; Corticospinal Tracts; Cytidine Diphosphate Diglycerides; Development; Disease; Drug Kinetics; Endoplasmic Reticulum; Exposure to; Fluoxetine; Goals; Growth; Growth Factor; Human; In Vitro; Injury; Knowledge; Laceration; Lead; Ligands; Link; Mechanics; Mediating; Mediator; Membrane; Modeling; Motor; Natural regeneration; Nerve Growth Factors; Nerve Regeneration; Nerve Tissue; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; PIK3CG gene; Paralysed; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipase C; Phosphorylation; Preparation; Program Sustainability; Proliferating; Property; Protein Isoforms; Ras Signaling Pathway; Rattus; Receptor Activation; Receptor Signaling; Recovery; Recovery of Function; Recycling; Research; Resistance; Role; SKF38393; Sampling; Sensory; Signal Transduction; Slice; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Testing; Therapeutic; Tissues; Traumatic injury; Work; axon injury; design; drug candidate; efficacy evaluation; experimental study; healing; member; nerve damage; nerve injury; nerve stem cell; neural; neural growth; neuronal survival; neurotrophic factor; novel; pharmacologic; programs; receptor; regenerative; regenerative repair; regenerative treatment; repaired; screening; small molecule; spinal cord repair; tissue culture; translational approach; uptake

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.

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，包括完整 严重病例的麻痹。严重的SCI目前无法治愈，因为没有药物可以逆转 与损伤有关的神经组织损伤。确实，与可以治愈和恢复功能的外周组织不同 裂缝和污染性伤害后，脊髓众所周知能够抗性或替换 受伤后与大脑的神经联系。这项研究的总体目标是增加理解 神经加续机制和发现科学治疗的新型药理学靶标。 动物模型中的实验表明，脊柱中神经生长因子的生物学活性 绳索可以将组织推向再生程序。我们制定了一种可以实现的策略 这种使用合成小分子化合物的提升。经过合理的选择和筛选几个 小分子化合物，我们发现几个成员可以有效地促进神经受损的再生 组织培养模型中的细胞。其中一些化合物被用作其他的批准药物 疾病和所有六种化合物都能够从血液中穿过中枢神经系统。共享 化合物的生化特性允许开发一个统一的假设，该假设将 这些非肽神经营养化合物具有生长因子信号传导和再生作用的途径。 我们认为，合乎逻辑的下一步是阐明这些化合物起作用的机制。完成 在该项目中提出的实验中，将产生应提高这种理解的结果。 此后，我们将利用所获得的知识开始努力重新利用现有药物或 设计新化合物，以促进神经细胞再生并修复受损的神经连接 治疗SCI患者。