In Vivo Reprogramming of Glial Fate for Spinal Cord Repair

描述(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。经常存活的患者生活在瘫痪中，生活质量和生产力极大下降。这给患者和他们的照顾者带来了巨大的经济和情感负担。目前还没有有效的治疗方法。这在很大程度上是因为脊髓损伤往往会导致神经元的永久性丧失和神经回路的中断。对于脊髓损伤后的功能恢复，关键挑战是如何恢复受损的神经元回路。这项拟议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脊髓损伤治疗策略。作为对损伤的反应，星形胶质细胞变得活跃并增殖，形成胶质瘢痕。这些疤痕最初是有益的，因为它保护了受损部位周围细胞的完整性。然而，它们的持久性不利于神经元的修复。神经胶质疤痕不仅形成物理屏障，而且还分泌轴突生长抑制因子，作用于存活的神经元。我们推测，将这些瘢痕形成细胞的命运改变为神经前体细胞和/或神经元，可能通过两种方式实现脊髓损伤的自我修复：1)通过解除胶质瘢痕对存活神经元轴突生长的抑制 2)通过转换新的神经元形成桥接神经回路。我们的初步数据表明，单个转录因子在成年脊髓中的异位表达可以诱导出新的神经元。这一建议的主要目标是：1)进一步研究成人脊髓的体内重编程过程；2)针对几种遗传和表观遗传途径来提高重编程效率；3)优化重编程过程，以实现神经元的存活、成熟和功能整合到局部神经元回路。这一建议的结果可能会导致一种新的脊髓损伤治疗策略，即让受损的脊髓利用内源性细胞进行自我修复。

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.