Defining and exploiting the plasticity transcriptome to repair the damaged spinal cord

定义和利用可塑性转录组来修复受损的脊髓

• 批准号: 10365477
• 负责人: William B. Cafferty
• 金额: $ 45.78万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365477
• 关键词: Acute; Adult; Affect; Anatomy; Atlases; Automobile Driving; Axon; Cells; Cervical; Chronic; Clinical; Contralateral; Corticospinal Tracts; Data; Data Set; Disease; Embryo; Emotional; Family; Foundations; Gene Expression Profiling; Genes; Genetic Transcription; Geometry; Goals; Growth; Growth Inhibitors; Harvest; Human; In Vitro; Injury; Intervention; Label; Lesion; Location; Lumbar spinal cord structure; Mediating; Modeling; Molecular; Molecular Target; Mus; Myelin; Natural regeneration; Neuraxis; Neurons; Optic Nerve; Pathway interactions; Patients; Phenotype; Population; Proteins; Recovery; Recovery of Function; Rehabilitation therapy; Research; Research Personnel; Retinal Ganglion Cells; Specificity; Spinal; Spinal cord damage; Spinal cord injury; Therapeutic; Therapeutic Intervention; Tissue-Specific Gene Expression; Tissues; Training; Trauma; Viral; Wild Type Mouse; axon growth; design; effective therapy; experience; functional plasticity; functional restoration; genetic signature; in vivo; induced pluripotent stem cell; injury burden; inositol-1,4,5-trisphosphate 5-phosphatase; lipid phosphate phosphatase; novel; novel therapeutics; patient prognosis; prevent; programs; receptor; repair strategy; repaired; response; single-cell RNA sequencing; transcriptome; transcriptome sequencing

SUMMARY A century of research has shown that the adult central nervous system is incapable of self-repair after injury or disease. Indeed, adults with 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 and particularly after intensive rehabilitative therapy. In this proposal we have used in vivo viral tracing in combination with FACS and single cell RNA sequencing to develop a comprehensive anatomical and molecular atlas of the adult corticospinal tract (CST). We plan to leverage this atlas to define the molecular mechanisms that drive axon growth in specific subsets of corticospinal tract neurons during rehab in the presence and absence of the axon growth inhibitors nogo receptor-1. We believe that a comprehensive understanding of the intrinsic molecular mechanism that initiates and sustains rehab-mediated axon growth within defined subsets of CST neurons can then be exploited to design novel therapies to repair the acutely and chronically damaged spinal cord.

总结 世纪的研究表明，成年人的中枢神经系统在损伤或损伤后不能自我修复。 疾病事实上，患有创伤性脊髓损伤的成年人保持慢性功能缺陷， 他们生活的方方面面。然而，越来越多的证据表明，成人中枢神经系统保留了一些启动能力， 一个成长计划和功能重组，以应对活动，经验和轻微的创伤， 特别是在强化康复治疗之后。在该提议中，我们使用了体内病毒追踪， 与FACS和单细胞RNA测序相结合，以开发一种全面的解剖和 成人皮质脊髓束（CST）的分子图谱。我们计划利用这个图谱来定义 在恢复过程中驱动皮质脊髓束神经元特定亚群轴突生长的机制 轴突生长抑制剂Nogo受体-1的存在和不存在。我们认为， 了解启动和维持rehab介导的轴突生长的内在分子机制 然后可以利用CST神经元的定义子集来设计新的疗法来修复急性损伤。 和长期受损的脊髓