PRG3 drives functional plasticity in intact circuits after spinal cord injury

PRG3 驱动脊髓损伤后完整回路的功能可塑性

• 批准号: 9230456
• 负责人: William B. Cafferty
• 金额: $ 36.64万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9230456
• 关键词: Acute; Adult; Attenuated; Automobile Driving; Axon; Biological Assay; CRISPR/Cas technology; Cells; Chronic; Clinical; Contusions; Data; Disease; Embryo; Emotional; Family; Genes; Goals; Growth; In Vitro; Injury; Knowledge; Lesion; Location; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Profiling; Motor; Motor Cortex; Motor Neurons; Mus; Natural regeneration; Neuraxis; Neurites; Neurons; Patients; Population; Rattus; Recovery; Recovery of Function; Research; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Specificity; Spinal; Spinal cord damage; Spinal cord injury; Testing; Therapeutic; Trauma; Viral; adeno-associated viral vector; axon growth; central nervous system injury; crystallin mu; design; differential expression; effective therapy; experience; experimental study; functional plasticity; functional restoration; in vivo; injury burden; insight; knock-down; mutant; neurite growth; novel; novel strategies; novel therapeutics; outcome forecast; overexpression; programs; public health relevance; repaired; response; screening; transcriptome sequencing

 DESCRIPTION (provided by applicant): More than 100 years of research has shown that the adult central nervous system is incapable of self-repair after injury or disease. Indeed, adults that suffer traumatic spinal cord injuries maintain chronic functional deficits that impact all aspects of their lives. However, increasing evidence suggests that the adult CNS retains some ability to initiate a growth program and functionally re-organize in response to activity, experience and mild trauma. In this proposal we have specifically isolated adult CNS neurons that have initiated an intrinsic growth response and after completing next generating sequencing (RNAseq), we have identified Plasticity Related Gene-3 (PRG3) as a novel cell autonomous mediator of axon growth. We have designed experiments to understand the molecular mechanisms underlying PRG3-mediated axon growth and plan to assess whether exploiting this molecular machinery can enhance functional recovery after severe acute and chronic experimental spinal cord injury in vivo. We believe that a comprehensive understanding of the intrinsic molecular mechanism that initiates and sustains spontaneous axon growth in adult CNS neurons can then be exploited to design novel therapies to repair the damaged spinal cord.

 100多年的研究表明，成人中枢神经系统在受伤或疾病后无法自我修复。事实上，遭受创伤性脊髓损伤的成年人保持着影响他们生活各个方面的慢性功能缺陷。然而，越来越多的证据表明，成年人的中枢神经系统保留了一些能力，启动一个生长程序和功能重组的活动，经验和轻微的创伤。在该提案中，我们专门分离了已启动内在生长反应的成年CNS神经元，并在完成下一代测序（RNAseq）后，我们鉴定了可塑性相关基因-3（PRG 3）作为轴突生长的新型细胞自主调节剂。我们设计了实验来了解PRG 3介导的轴突生长的分子机制，并计划评估利用这种分子机制是否可以增强体内严重急性和慢性实验性脊髓损伤后的功能恢复。我们相信，全面了解内在的分子机制，启动和维持自发轴突生长的成年中枢神经系统神经元，然后可以利用设计新的治疗方法来修复受损的脊髓。