In Vivo Reprogramming of Glial Fate for Spinal Cord Repair

体内神经胶质命运重编程用于脊髓修复

• 批准号: 9050713
• 负责人: Chun-Li Zhang
• 金额: $ 34.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050713
• 关键词: Adult; Astrocytes; Brain; Brain-Derived Neurotrophic Factor; Bypass; CDKN2A gene; Caregivers; Cell Transplantation; Cells; Cellular biology; Chromatin; Cicatrix; Contusions; Data; Ectopic Expression; Electrophysiology (science); Emotional; Epigenetic Process; Event; Genetic; Goals; Health; Histones; Immunohistochemistry; Injury; Lead; Life; Modeling; Morbidity - disease rate; Mus; Natural regeneration; Nature; Neuroglia; Neurons; Outcome; Paralysed; Pathway interactions; Patients; Process; Productivity; Proliferating; Quality of life; Recovery of Function; Research; Role; Site; Source; Spinal; Spinal Cord; Spinal cord damage; Spinal cord injury; Therapeutic; Valproic Acid; axon growth; base; improved; in vivo; inhibitor/antagonist; injured; innovation; mortality; nerve stem cell; neural circuit; neuroblast; neuron loss; neuronal circuit disruption; neuronal circuitry; neuronal survival; novel therapeutics; relating to nervous system; repaired; response to injury; spinal cord repair; transcription factor

DESCRIPTION (provided by applicant): Severe morbidity and mortality are commonly associated with spinal cord injury (SCI). Patients who survive frequently live with paralysis and extremely reduced quality of life and productivity. The financial and emotional burdens to patients and their caregivers are enormous. There is currently no effective cure. This is largely because SCI often results in a permanent loss of neurons and the disruption of neural circuits. For a functional recovery after SCI, the key challenge is how to restore the disrupted neuronal circuits. The long-term goal of this proposed research is to develop an innovative therapeutic strategy for SCI by using patients' endogenous cells. In response to injury, astrocytes become reactive and proliferate to form glial scars. These scars are initially beneficial by preserving th integrity of cells surrounding the damaged site. However, their persistence is detrimental to neuronal repair. Glial scars not only form a physical barrier but also secrete inhibitors of axon growth that act on surviving neurons. We hypothesize that changing the fate of these scar- forming cells to neural progenitors and/or neurons might enable self-repair of the injured spinal cord in two ways: 1) by relieving the inhibition of axon growth of surviving neurons by glial scars and 2) by the formation of bridging neural circuits through converted new neurons. Our preliminary data shows that new neurons can be induced by the ectopic expression of a single transcription factor in the adult spinal cord. The major goals of this proposal are 1) to further examine the in vivo reprogramming process in the adult spinal cord, 2) to target several genetic and epigenetic pathways to enhance the reprogramming efficiency, and 3) to optimize the reprogramming process for neuronal survival, maturation and functional integration into the local neuronal circuitry. Results from this proposal may lead to a novel therapeutic strategy for SCI, which is to let the injured spinal cord repair itself using endogenous cells.

描述（由申请人提供）：严重的发病率和死亡率通常与脊髓损伤（SCI）有关。存活下来的患者经常瘫痪，生活质量和生产力极度下降。患者及其护理人员的经济和情感负担是巨大的。目前没有有效的治疗方法。这在很大程度上是因为SCI经常导致神经元的永久性丧失和神经回路的中断。对于SCI后的功能恢复，关键的挑战是如何恢复中断的神经元回路。这项研究的长期目标是通过使用患者的内源性细胞来开发一种创新的SCI治疗策略。在对损伤的反应中，星形胶质细胞变得具有反应性并增殖以形成神经胶质瘢痕。这些疤痕最初是有益的，因为它可以保护受损部位周围细胞的完整性。然而，它们的持续存在对神经元修复是有害的。胶质瘢痕不仅形成物理屏障，而且还分泌作用于存活神经元的轴突生长抑制剂。我们假设，改变这些瘢痕形成细胞的命运，使其成为神经祖细胞和/或神经元，可能通过两种方式使受损脊髓自我修复：1）通过减轻胶质瘢痕对存活神经元轴突生长的抑制 和2）通过转换的新神经元形成桥接神经回路。我们的初步数据表明，新的神经元可以诱导在成年脊髓中的一个单一的转录因子的异位表达。该提议的主要目标是：1）进一步检查成人脊髓中的体内重编程过程，2）靶向几种遗传和表观遗传途径以提高重编程效率，以及3）优化重编程过程以使神经元存活、成熟和功能整合到局部神经元回路中。这一建议的结果可能导致一种新的SCI治疗策略，即让受损的脊髓利用内源性细胞进行自我修复。