Strategies to interrogate and enhance myelin remodeling in distal tissue after spinal cord injury

每年有成千上万的人遭受脊髓损伤（SCI），仅在美国就有成千上万的人长期生活在与SCI相关的缺陷中。令人沮丧的是，很少有成功的干预措施，特别是对于那些受伤几个月到几年的人。无论是对脊髓损伤的理解还是对治疗靶点的开发，脊髓损伤领域都主要集中在直接病变区域。然而，目前的干预措施，如硬膜外刺激和跑步机康复，最常针对的是远离直接损伤部位的“备用”组织。虽然以前的研究已经探索了这些远端区域内神经元和轴突的变化，但胶质反应在很大程度上被忽视了。因此，本研究将探讨脊髓损伤后远端少突胶质细胞祖细胞（OPCs）和新髓鞘的形成。OPCs是成人中枢神经系统中大量的增殖性胶质细胞，已知它们对损伤的反应是增殖并分化为髓鞘少突胶质细胞。新髓磷脂的形成也是成人大脑回路调节的一个重要因素。此外，这些细胞的长期再生能力使它们在最初的脊髓损伤后很长一段时间内成为理想的干预目标。众所周知，脊髓损伤增加了OPC的增殖和分化，以及病变区域附近新髓鞘的形成。这些过程是如何在远端组织中展开的，在那里电路重组正在发生，在此尚未探索。这一建议旨在建立一个更完整的神经胶质参与脊髓损伤后神经回路调节的图景。此外，我们将探讨中胸和颈椎损伤的这些变化，使我们能够对脊髓损伤的临床相关模型进行比较。该建议的第一个目标是询问在多大程度上少突胶质细胞的发生和髓鞘形成在这些远端组织中被改变，包括脊髓区域，病变的吻侧和尾侧以及大脑。这也将从脊髓损伤后的早期到晚期进行探讨，以确定新髓鞘形成对远端组织长期变化的影响程度。第二个目标是明确表征opc -神经元的相互作用。这些相互作用以前未在脊髓中被探索过，更不用说在脊髓损伤的背景下了。该实验将为脊髓opc -神经元的相互作用如何被损伤调节建立一个核心的理解。最终目标是利用自愿运动的治疗相关干预来探索新髓磷脂形成和opc -神经元相互作用在当前康复策略中的作用。总的来说，该应用旨在促进对脊髓损伤的基本理解，特别是远端组织随时间的调节。这些研究可以进一步强调新髓磷脂形成在运动干预中的重要性，并作为改善脊髓损伤后慢性缺陷的治疗靶点。

Thousands of people a year receive a spinal cord injury (SCI) and there are hundreds of thousands of individuals living with long-term SCI-related deficits in the United States alone. Frustratingly, there are very few successful interventions, particularly for people who are months to years out from their injury. The SCI field has largely focused on the immediate lesion area in terms of both understanding SCI and developing therapeutic targets. It is, however, “spared” tissue distant from the immediate site of injury that is most often targeted with current interventions such as epidural stimulation and treadmill-based rehabilitation. While previous studies have explored changes in neurons and axons within these distal regions, the glial response has largely been overlooked. Therefore, this study will interrogate oligodendrocyte progenitor cells (OPCs) and new myelin formation in distal regions after SCI. OPCs are a large pool of proliferative glia within the adult central nervous system, and are known to respond to insults by proliferating and differentiating into myelinating oligodendrocytes. New myelin formation is also emerging as an important factor in circuit modulation in the adult brain. Furthermore, the long-term regenerative capacity of these cells makes them an ideal target for intervention long after the initial SCI. It is known that SCI increases in OPC proliferation and differentiation, as well as new myelin formation near the lesion area. How these processes unfold in distal tissue, where circuit reorganization is occurring, is hereto unexplored. This proposal intends to build a far more complete picture of glial involvement in circuit modulation after SCI. Furthermore, we will interrogate these changes in both mid-thoracic and cervical injuries, allowing us to make comparisons between clinically relevant models of SCI. The first goal of this proposal is to interrogate to what extent oligodendrocyte genesis and myelin formation are altered in these distal tissues, including spared spinal cord regions rostral and caudal to the lesion as well as the brain. This will also be explored from early through late time points after SCI to determine the extent to which new myelin formation contributes to long-term changes in distal tissues. The second goal is to specifically characterize OPC-neuronal interactions. These interactions have been previously unexplored in the spinal cord, let alone in the context of SCI. This experiment would build a core understanding of how spinal cord OPC-neuronal interactions are modulated by injury. The final goal is to use the therapeutically relevant intervention of voluntary exercise to explore the roles new myelin formation and OPC-neuron interactions play in current rehabilitation strategies. Overall, this application aims to contribute to the fundamental understanding of SCI, particularly the modulation of distal tissues over time. These studies could further underscore the importance of new myelin formation in exercise-based interventions and as a therapeutic target for improving deficits chronically after SCI.