Harnessing Corticospinal Axon Sprouting for Functional Recovery in Chronic Injury

退伍军人管理局每年治疗超过26,000名脊髓损伤(SCI)和疾病患者，使 该部门是世界上最大的提供脊髓护理的医疗保健系统。更好地理解 中枢神经系统(CNS)损伤后的轴突修复是康复治疗发展的关键 适用于脊髓损伤患者，尤其是慢性伤者。这项建议的首要目标是理解 如何加强和利用轴突萌发，这是中枢神经系统的一种内源性修复机制 促进慢性脊髓损伤患者的功能恢复。拟议研究的一个重要前提是轴突 未受损伤的神经元发芽是一种重要的、容易获得的轴突修复形式，它将 与更具挑战性的促进再生相比，可能会产生近期的翻译价值 战略。以往对轴突萌发的研究主要集中在脊髓损伤的急性期或亚急性期。海流 赠款机制将鼓励我们深入研究轴突发芽与慢性损伤的重要生物学。 这一建议建立在我们最近发表的关于年龄对中枢神经系统轴突再生和 我们未发表的关于年龄和慢性损伤在轴突修复中的影响的初步数据。使用鼠标 以皮质脊髓束(CST)为模型系统，我们将检验萌发可以发生和 有助于慢性脊髓损伤的功能恢复，这种内源性修复机制可以得到加强 通过对慢性损伤的中枢神经系统进行分子干预。我们将采用单侧锥体切开损伤模型 这就切断了CST的一侧，用于研究从中线到失神经一侧的萌发。我们将评估 慢性损伤小鼠CST轴突萌发的水平，并确定有效的分子操作 在慢性损伤的小鼠中促进这种发芽。我们还将把促进发芽的战略和 康复训练以促进慢性脊髓损伤后的功能恢复。总而言之，建议的 研究将探讨轴突萌发作为一种潜在的更容易获得的修复机制的潜力 促进慢性脊髓损伤后功能恢复。

VA treats more than 26,000 people with spinal cord injury (SCI) and disorders each year, making the department the largest health care system in the world providing spinal cord care. A better understanding of axonal repair after central nervous system (CNS) injury is critical to the development of restorative treatment for people with SCI, especially the chronically injured. The overarching goal of this proposal is to understand how axonal sprouting, a form of endogenous repair mechanism in the CNS, can be enhanced and harnessed to promote functional recovery in chronic SCI. An important premise of the proposed study is that axonal sprouting from uninjured neurons represents an important and readily accessible form of axonal repair that will likely generate near-term translational value as compared to the more challenging regeneration-promoting strategies. Previous studies of axonal sprouting have focused on acute or subacute phases of SCI. The current grant mechanism will encourage us to delve into the important biology of axonal sprouting with chronic injury. This proposal builds upon our very recent published study on the impact of age on CNS axon regeneration and our unpublished preliminary data on the effect of age and chronic injury in axonal repair. Using the mouse corticospinal tract (CST) as the model system, we will test the hypothesis that sprouting can occur and contribute to functional recovery in chronic SCI, and that this endogenous repair mechanism can be enhanced through molecular intervention in the chronically injured CNS. We will use unilateral pyramidotomy injury model that severs one side of the CST to study sprouting across the midline to the denervated side. We will assess the level of CST axon sprouting in chronically injured mice, and identify effective molecular manipulations that promote such sprouting in chronically injured mice. We will also combine sprouting-promoting strategies and rehabilitative training to enhance functional recovery after a chronic spinal cord injury. Together, the proposed studies will address the potential of axon sprouting as a potentially more accessible repair mechanism to promote recovery of function in chronic SCI.