In vivo reprogramming of reactive astrocyte and chemogenetic approach for SCI repair.

反应性星形胶质细胞的体内重编程和用于 SCI 修复的化学遗传学方法。

• 批准号: 10176608
• 负责人: QI LIN CAO
• 金额: $ 5.62万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176608
• 关键词: Adult; Astrocytes; Axon; Binding; Brain-Derived Neurotrophic Factor; Chondroitin Sulfate Proteoglycan; Chronic; Cicatrix; Contusions; Corticospinal Tracts; Dependovirus; Emotional; Environment; Event; Excision; Genetic; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections; Injury; Label; Methods; Molecular; Monitor; Motor; Mus; NTF3 gene; Natural regeneration; Neuronal Differentiation; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Neurotrophic Tyrosine Kinase Receptor Type 3; Paralysed; Patients; Phenotype; Productivity; Quality of life; Recovery of Function; Role; Serotyping; Spinal cord injury; Spinal cord injury patients; Technology; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Viral; Work; astrogliosis; axon injury; axon regeneration; axonal degeneration; base; effective therapy; functional loss; in vivo; inhibitor/antagonist; injured; injury and repair; nerve stem cell; neural graft; novel; novel strategies; repaired; reticulospinal tract; transcription factor

Spinal cord injury (SCI) is a devastating event resulting in enormous physical and emotional suffering in patients. SCI patients often live with paralysis and extremely reduced quality of life and productivity. Therapeutic intervention(s) to restore even partial function would significantly increase the quality of life for those patients. Axonal degeneration significantly contributes to functional loss after SCI. Unfortunately, axons in the adult mammalian CNS fail to regenerate after injury due to the non-permissive environment formed primarily by astroglial scars. Astroglial scars not only form a physical barrier, but they also secrete inhibitors, such as chondroitin sulfate proteoglycans (CSPGs), to inhibit the regrowth of injured axons. Previous studies show that degradation of CSPGs, or application of its antagonists, can promote axonal regeneration after SCI. However, these methods only temporarily remove the inhibitory CSPG and are very limited in promoting axonal regeneration and functional recovery after SCI. In this study, we will use novel genetic methods to permanently change the fate of astroglial scars to enhance self-repair of axons after SCI. We hypothesize that in vivo reprogramming of the inhibitory reactive astrocytes into neurons will promote functional recovery after SCI by two synergistic mechanisms: 1) decreasing the astrogliosis and its inhibition to promote regeneration of descending motor tracts; and 2) forming neuronal relay reconnecting the injured descending axons and its caudal target neurons. We will test these hypotheses using three specific aims. Aim 1 will examine in vivo reprogramming of reactive astrocytes after SCI. We hypothesize that forced expression of phenotype specific transcription factors will convert the inhibitory reactive astrocytes into neurons which could integrate into host circuits. Aim 2 will examine whether in vivo astrocyte reprogramming will promote axonal regeneration and functional recovery after SCI. Aim 3 will examine whether combination of in vivo astrocyte reprogramming with multineurotrophin D15A will further promote axonal regeneration and functional recovery after chronic SCI. The proposed studies will help us evaluate the therapeutic potential of in vivo astrocyte reprogramming after SCI and understand the mechanisms of this novel approach for functional recovery. These studies could help us develop the much-needed novel effective therapies for SCI.

脊髓损伤（SCI）是一种毁灭性的事件，导致巨大的身体和情感痛苦， 患者SCI患者通常瘫痪，生活质量和生产力极度下降。 即使是恢复部分功能的治疗干预也会显著提高患者的生活质量。 这些病人。脊髓损伤后轴突变性是导致功能丧失的重要原因。不幸的是，轴突 在成年哺乳动物中，由于所形成的非容许环境， 主要是通过星形胶质细胞的疤痕星形胶质细胞瘢痕不仅形成物理屏障，而且它们还分泌抑制剂， 如硫酸软骨素蛋白聚糖（CSPG），以抑制受损轴突的再生。以前的研究 表明CSPGs降解或其拮抗剂的应用可促进SCI后轴突再生。 然而，这些方法仅暂时去除抑制性CSPG，并且在促进轴突生长方面非常有限。 脊髓损伤后的再生和功能恢复。在这项研究中，我们将使用新的遗传方法， 改变星形胶质细胞疤痕的命运，以增强SCI后轴突的自我修复。我们假设在体内 将抑制性反应性星形胶质细胞重编程为神经元将促进SCI后的功能恢复， 两种协同机制：1）减少星形胶质细胞增生并抑制其增殖，促进再生， 下行运动束; 2）形成神经元中继，重新连接受损的下行轴突及其 尾部靶神经元我们将用三个具体目标来检验这些假设。目的1将在体内检测 SCI后反应性星形胶质细胞的重编程。我们假设，表型特异性的强制表达 转录因子将抑制性反应性星形胶质细胞转化为神经元， 电路.目的2将研究体内星形胶质细胞重编程是否会促进轴突再生， SCI后功能恢复目的3将检查体内星形胶质细胞重编程与 多神经营养因子D15 A将进一步促进慢性SCI后的轴突再生和功能恢复。的 提出的研究将帮助我们评估SCI后体内星形胶质细胞重编程的治疗潜力 并了解这种新的功能恢复方法的机制。这些研究可以帮助我们 为SCI开发急需的新的有效疗法。