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

基本信息

批准号：
7845518
负责人：
Damien D. Pearse
金额：
$ 33.13万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845518
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

项目摘要

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、一次性将 cAMP 注射到植入物上方和下方的脐带以及两周皮下输注 Rolipram 的三重组合可诱导血清素能细胞的大量生长。纤维进入植入物并超出植入物尾部的绳索。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。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chronic spinal hemisection in rats induces a progressive decline in transmission in uninjured fibers to motoneurons.

DOI：
10.1016/j.expneurol.2009.01.004
发表时间：
2009-04
期刊：
EXPERIMENTAL NEUROLOGY
影响因子：
5.3
作者：
Arvanian, Victor L.;Schnell, Lisa;Lou, Li;Golshani, Roozbeh;Hunanyan, Arsen;Ghosh, Arko;Pearse, Damien D.;Robinson, John K.;Schwab, Martin E.;Fawcett, James W.;Mendell, Lorne M.
通讯作者：
Mendell, Lorne M.

Acute Putrescine Supplementation with Schwann Cell Implantation Improves Sensory and Serotonergic Axon Growth and Functional Recovery in Spinal Cord Injured Rats.

急性腐胺补充与雪旺细胞植入可改善脊髓损伤大鼠的感觉和血清素轴突生长和功能恢复。

DOI：
10.1155/2015/186385
发表时间：
2015
期刊：
Neural plasticity
影响因子：
3.1
作者：
Iorgulescu,JBryan;Patel,SamikP;Louro,Jack;Andrade,ChristianM;Sanchez,AndreR;Pearse,DamienD
通讯作者：
Pearse,DamienD

Extensive cell migration, axon regeneration, and improved function with polysialic acid-modified Schwann cells after spinal cord injury.

DOI：
10.1002/glia.22330
发表时间：
2012-05
期刊：
GLIA
影响因子：
6.2
作者：
Ghosh, Mousumi;Tuesta, Luis M.;Puentes, Rocio;Patel, Samik;Melendez, Kiara;El Maarouf, Abderrahman;Rutishauser, Urs;Pearse, Damien Daniel
通讯作者：
Pearse, Damien Daniel

MASH1/Ascl1a leads to GAP43 expression and axon regeneration in the adult CNS.

DOI：
10.1371/journal.pone.0118918
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Williams RR;Venkatesh I;Pearse DD;Udvadia AJ;Bunge MB
通讯作者：
Bunge MB

The therapeutic profile of rolipram, PDE target and mechanism of action as a neuroprotectant following spinal cord injury.

DOI：
10.1371/journal.pone.0043634
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Schaal SM;Garg MS;Ghosh M;Lovera L;Lopez M;Patel M;Louro J;Patel S;Tuesta L;Chan WM;Pearse DD
通讯作者：
Pearse DD