Axon Regenration: Synergistic Actions of the MAPK and Cyclic AMP Pathways

轴突再生：MAPK 和环 AMP 通路的协同作用

• 批准号: 7615018
• 负责人: Damien D. Pearse
• 金额: $ 33.47万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7615018
• 关键词: Adult; Animals; Axon; Axonal Transport; Behavioral; Brain Stem; Brain-Derived Neurotrophic Factor; Cell model; Clinical; Combined Modality Therapy; Contusions; Cyclic AMP; Devices; Distal; Electric Stimulation; Evaluation; Exhibits; Fiber; Future; Goals; Growth; Hindlimb; Human; Implant; Infusion procedures; Injection of therapeutic agent; Injury; Interruption; Intervention; Lead; Lesion; Location; Locomotion; MAP Kinase Gene; Maps; Measurement; Measures; Methylprednisolone; Modeling; Neuroglia; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; Pathway interactions; Performance; Population; Rattus; Recovery; Recovery of Function; Reflex action; Research; Research Design; Role; Rolipram; Route; Schwann Cells; Sensory; Serotonin; Signal Transduction; Site; Spinal; Spinal Cord; Spinal cord injury; Test Result; Testing; Therapeutic Intervention; Time; Transplantation; Ventral Roots; Walking; axon growth; behavior test; central pattern generator; conditioning; effective therapy; falls; functional improvement; immunocytochemistry; implantation; improved; injured; millimeter; myelination; neuronal cell body; neurotrophic factor; novel; raphe nuclei; receptor; repaired; research study; response; restoration; subcutaneous; white matter

DESCRIPTION (provided by applicant): Our ultimate goal is to develop effective strategies to improve outcome after human spinal cord injury (SCI). We have demonstrated (Pearse et al., 2004) that a triple combination of a SC implant, a one-time injection of cAMP into the cord above and below the implant, and a two-week subcutaneous infusion of Rolipram induced substantial growth of serotonergic fibers into the implant and beyond into the cord caudal to the implant. A marked improvement in locomotor test scores was observed in groups with the best growth of serotonergic axons in the caudal cord. To build on these results, we propose three Specific Aims using the same injury model and SC grafting (Pearse et al., 2004). In Aim 1, we will determine the most effective delivery site (lesion, raphe somata, or both) for cAMP elevation (by measuring fibers and evaluating locomotion). BDNF is known also to promote growth of serotonergic axons into the cord caudal to a SC graft; therefore we will determine the most efficacious site for BDNF delivery using the same SCI paradigm. In Aim 2, we propose to test the possibility that the combination of cAMP elevation and BDNF administration will be more effective than either one alone. Administration of cAMP (best route) and BDNF (best route) will be combined and the serotonergic axon growth response compared to that observed with either factor alone. Behavioral test results will be correlated with axon growth in each animal. In Aim 3, we propose to determine the functionality of the serotonergic projections after our most effective treatment. First, changes in locomotion caused by pharmacologically blocking serotonergic receptors will be assessed. Second, we will determine reflex responses to somatic afferent stimulation following electrical stimulation of raphespinal pathways. Third, the release of 5-HT by descending fibers after the best treatment will be verified. Exploration of combined therapies to improve serotonergic fiber growth beyond the site of injury and determination of the role of the potentially improved growth on locomotion will lead to new clinical strategies in the future.

描述（由申请人提供）：我们的最终目标是制定有效的策略来改善人类脊髓损伤（SCI）后的结果。 我们已经证明（Pearse 等人，2004），SC 植入物、一次性向植入物上方和下方的脐带注射 cAMP 以及两周皮下注射咯利普兰 (Rolipram) 的三重组合可诱导血清素能纤维大量生长到植入物中，并超出植入物尾部的脐带。 在尾索中血清素能轴突生长最好的组中观察到运动测试分数的显着改善。 为了以这些结果为基础，我们使用相同的损伤模型和 SC 移植提出了三个具体目标（Pearse 等，2004）。 在目标 1 中，我们将确定 cAMP 升高最有效的递送部位（病变、中缝体或两者）（通过测量纤维和评估运动）。 BDNF 还可以促进 5-羟色胺能轴突生长到 SC 移植物尾部的脊髓中；因此，我们将使用相同的 SCI 范式确定 BDNF 传递最有效的位点。 在目标 2 中，我们建议测试 cAMP 升高和 BDNF 联合给药比单独使用任何一种更有效的可能性。 cAMP（最佳途径）和 BDNF（最佳途径）的施用将结合起来，并且将血清素能轴突生长反应与单独使用任一因子观察到的结果进行比较。 行为测试结果将与每只动物的轴突生长相关。 在目标 3 中，我们建议在最有效的治疗后确定血清素能预测的功能。 首先，将评估药物阻断血清素受体引起的运动变化。 其次，我们将确定中缝脊髓通路电刺激后对躯体传入刺激的反射反应。 第三，将验证最佳处理后下行纤维释放5-HT的情况。 探索联合疗法以改善损伤部位以外的血清素纤维生长，并确定潜在改善的生长对运动的作用，将在未来带来新的临床策略。