Develop a combinatorial therapy for spinal cord injury

开发脊髓损伤的组合疗法

基本信息

批准号：
10189722
负责人：
SHUXIN LI
金额：
$ 34.29万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189722
关键词：
Adult Afferent Neurons Antibodies Axon CD45 Antigens Chest Chondroitin Sulfate Proteoglycan Cicatrix Combined Modality Therapy Corticospinal Tracts Development Dorsal Environment Failure Family Fiber Genetic Goals Growth Individual Injury Knock-out Knockout Mice LAR tyrosine phosphatase receptor Lesion Locomotion Locomotor Recovery Mammals Mediating Modeling Molecular Target Movement Mus Natural regeneration Nerve Regeneration Neuronal Plasticity Neurons Peptides Pharmacology Phosphoric Monoester Hydrolases Pilot Projects Play Population Projection Positioning Attribute Protein Tyrosine Phosphatase Rattus Receptor Signaling Recovery Recovery of Function Rodent Role Sensory Signal Pathway Signal Transduction Site Spinal Cord Contusions Spinal cord injury The Jackson Laboratory Therapeutic Transgenic Organisms Treatment Effectiveness WNT Signaling Pathway axon growth axon guidance axon injury axon regeneration base central nervous system injury combinatorial compare effectiveness design effectiveness evaluation extracellular in vivo inhibitor/antagonist injured injury and repair neuronal growth novel strategies optimal treatments receptor repair strategy sigma receptors synaptogenesis synergism treatment optimization

项目摘要

Project Summary Severed CNS axons fail to regenerate largely because of the reduced intrinsic growth capacity of adult neurons and poor environment for axon extension. The Co-I's Lab finds that the Wnt family molecules and their receptors are upregulated after spinal cord injury (SCI) and mediates regrowth Among adult failure of injured fiber tracts. several Wnt receptors, Ryk is crucial for mediating repulsive axon growth during development and in CNS after injury.Chondroitin sulfate proteoglycans (CSPGs) generated by glial scars strongly suppress axon extension and are major extrinsic molecular targets for treating CNS injury. The PI's group designed small peptides to block functions of CSPG receptors LAR and PTPσ by targeting their critical activity domains and demonstrated their high efficiency for promoting axon growth. Blocking each of the two receptors with 3 combined peptides promotes robust regeneration of injured CNS axons. We hypothesize that inhibiting both Wnt and CSPG signals represents a dual approach of enhancing neuronal growth capacity and reducing environmental inhibitory influence at the lesion site. We propose to stimulate robust axon regrowth in adult rodents with transection or contusion SCI by inhibiting Ryk and LAR/PTPσ with genetic and pharmacological approaches available in our labs. In Aim 1, we will study synergistic actions of transgenically deleting Ryk plus each of LAR/PTPσ receptors on promoting axon regeneration and recovery in mice with SCI. We will determine whether deleting Ryk plus LAR or Ryk plus PTPσ receptors acts synergistically to stimulate axon growth and enhance neuronal plasticity in double knockout mice after SCI. In Aim 2, we will determine whether blocking each of Ryk, LAR and PTPσ receptors with antibody or selective antagonists pharmacologically promotes axon regeneration and recovery in adult rats with SCI. We will compare effectiveness of the treatments that target individual receptors in promoting regrowth of multiple descending tracts and recovery of locomotor functions after SCI. In Aim 3, we will study whether combination therapies that block two or three receptors yield better axon regrowth and functional recovery in rats with transection or contusion SCI, aiming to identify the optimal therapy for mammals with SCI. Based on the promising results from our pilot studies, we predict that our combined strategies will promote dramatic regeneration of injured axon tracts and recovery of locomotion function in vivo. Our novel strategy of administering deliverable compounds post-injury may facilitate development of a practical combinatorial therapy for CNS lesions.

项目摘要切断的中枢神经系统轴突无法再生，这主要是因为成人的内在生长能力降低神经元和轴突延伸的环境不佳。二世实验室发现Wnt家族分子及其脊髓损伤（SCI）后受体上调并介导改革之中成人受伤的纤维区域失败。几个Wnt接收器RYK对于介导开发过程和中的排斥轴突生长至关重要受伤后的中枢神经系统。硫酸根硫酸盐蛋白聚糖（CSPGS）由神经胶质疤痕产生强烈抑制轴突延伸是治疗中枢神经系统损伤的主要外部分子靶标。 PI的组设计小肽通过靶向其关键活动域来阻止CSPG接收器的功能LAR和PTPσ的功能并证明了它们在促进轴突生长方面的高效率。用3阻断两个受体中的每个受体组合的宠物促进了受伤的中枢神经系统轴突的强大再生。我们假设抑制两者 Wnt和CSPG信号代表了增强神经元生长能力和降低的双重方法病变部位的环境抑制作用。我们建议在成人中刺激强大的轴突遗憾用遗传和药物抑制RYK和LAR/PTPσ，具有翻译或挫伤SCI的啮齿动物我们的实验室中可用的方法。在AIM 1中，我们将研究违反Ryk Plus的跨理学删除的协同行动 SCI小鼠促进轴突再生和恢复的每种LAR/PTPσ受体。我们将确定删除RYK Plus LAR或RYK PlusPTPσ受体是否具有协同作用以刺激轴突 SCI后双基因敲除小鼠的生长并增强神经元可塑性。在AIM 2中，我们将确定是否用抗体或选择性拮抗剂阻止RYK，LAR和PTPσ受体的药物促进具有SCI的成年大鼠的轴突再生和恢复。我们将比较针对个人接收者的治疗方法，以促进多个下降区的遗憾和恢复 SCI后的运动功能。在AIM 3中，我们将研究阻塞两到三个的组合疗法接收者在翻译或挫伤科学的大鼠中产生更好的轴突改革和功能恢复，旨在确定SCI哺乳动物的最佳疗法。根据我们的试点研究的承诺结果，我们预测我们的综合策略将促进受伤的轴突区域的戏剧性再生和恢复体内运动功能。我们管理可交付的化合物的新型策略可能促进开发用于中枢神经系统病变的实用组合疗法。