Mechanisms of corticospinal tract regeneration

皮质脊髓束再生机制

• 批准号: 10451151
• 负责人: OSWALD STEWARD
• 金额: $ 15.2万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451151
• 关键词: Adolescent; Adult; Animals; Axon; Axotomy; Brain; Cells; Consensus; Corticospinal Tracts; Dendrites; Development; Distal; Exhibits; FRAP1 gene; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Goals; Growth; Human; Injections; Injury; Intervention; Label; Lead; Light; LoxP-flanked allele; Maps; Microscopy; Molecular; Molecular Target; Motor Neurons; Mus; Natural regeneration; Nervous system structure; Neurodegenerative Disorders; Neuronal Injury; Neurons; PTEN gene; Paralysed; Pathway interactions; Phenotype; Protein Biosynthesis; Proteins; Proto-Oncogene Proteins c-akt; Rattus; Recovery; Regenerative response; Signal Pathway; Site; Sorting - Cell Movement; Specificity; Spinal Cord; Spinal cord injury; Technology; Testing; Therapeutic Intervention; Transfection; Transgenic Mice; Translations; Visualization; axon injury; axon regeneration; base; cell growth; central nervous system injury; connectome; genetic manipulation; knock-down; motor function recovery; neuronal growth; novel; repaired; response; retrograde transport; small hairpin RNA; spinal pathway; transcriptome; transcriptome sequencing

This project is dedicated to discovering ways to induce regeneration of the corticospinal tract (CST and recovery of motor function after spinal cord injury (SCI). The CST is the pathway that is responsible for the ability to move voluntarily. Damage to the CST as a result of a spinal cord injury is the reason people are paralyzed. The project is based on discoveries that the CST can be induced to regenerate following spinal cord injury by targeting molecular pathways that control cell growth in development, specifically phosphatase and tensin homolog (PTEN). PTEN is responsible for shutting down the type of protein synthesis that is critical for cell growth during development. PTEN acts by blocking the mammalian target of Rapamycin, (mTOR), so deletion of PTEN releases inhibition on mTOR, which in turn allows the cell to synthesize proteins that are critical for cell growth. We have shown that genetic deletion of PTEN in mice and knockdown of PTEN in rats with AAVshRNA allows CST neurons to mount a robust regenerative response, which is accompanied by recovery of motor function. The new project is based on exciting and novel recent discoveries that targeting PTEN in adult nerve cells induces a state of youthful vigor in which there is perpetual growth in addition to an ability to regenerate after injury. The overall goal of the project is to determine the cellular and molecular mechanisms of this growth-enabled state and identify the genes that are turned on or shut off during growth and regeneration. Defining the pattern of gene expression that underlies the growth-enabled state in nerve cells will identify targets for future therapeutic interventions to promote regeneration and repair after injury and potentially protect nerve cells from degeneration in neurodegenerative disorders.

该项目致力于发现诱导皮质脊髓束再生的方法 （CST 和脊髓损伤 (SCI) 后运动功能的恢复。CST 是 负责自主移动的能力。脊髓导致 CST 损伤 受伤是人们瘫痪的原因。该项目基于 CST 能够 通过靶向分子途径诱导脊髓损伤后再生 控制发育过程中的细胞生长，特别是磷酸酶和张力蛋白同源物 (PTEN)。 PTEN 负责关闭对细胞生长至关重要的蛋白质合成类型 发展。 PTEN 通过阻断雷帕霉素 (mTOR) 的哺乳动物靶点发挥作用，因此删除 PTEN 释放对 mTOR 的抑制，从而使细胞能够合成蛋白质 对细胞生长至关重要。我们已经证明，小鼠体内的 PTEN 基因缺失 在具有 AAVshRNA 的大鼠中敲低 PTEN 可使 CST 神经元建立强大的 再生反应，伴随着运动功能的恢复。新项目是 基于近期令人兴奋的新发现，针对成人神经细胞中的 PTEN 诱导 一种青春活力的状态，除了具有再生能力外，还能不断成长 受伤后。该项目的总体目标是确定细胞和分子 这种生长启用状态的机制并识别打开或关闭的基因 在生长和再生过程中。定义潜在的基因表达模式 神经细胞的生长促进状态将确定未来治疗干预的目标 促进损伤后的再生和修复，并可能保护神经细胞免受损伤 神经退行性疾病中的退化。