In Vivo Reprogramming of Glial Fate for Spinal Cord Repair

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。存活下来的患者往往会瘫痪，生活质量和工作效率也会大大降低。这给患者及其护理人员带来了巨大的经济和情感负担。目前尚无有效的治疗方法。这在很大程度上是因为脊髓损伤通常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，关键的挑战是如何恢复被破坏的神经元回路。这项研究的长期目标是利用患者的内源性细胞开发一种创新的脊髓损伤治疗策略。在对损伤的反应中，星形胶质细胞变得反应性和增殖形成胶质疤痕。这些疤痕最初是有益的，因为它保留了受损部位周围细胞的完整性。然而，它们的持续存在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剂，作用于存活的神经元。我们假设，将这些瘢痕形成细胞的命运改变为神经祖细胞和/或神经元可能通过两种方式实现损伤脊髓的自我修复：1)通过缓解胶质瘢痕对存活神经元轴突生长的抑制

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.