Harnessing Corticospinal Axon Sprouting for Functional Recovery in Chronic Injury

利用皮质脊髓轴突萌芽促进慢性损伤的功能恢复

• 批准号: 10929290
• 负责人: Binhai Zheng
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10929290
• 关键词: Acute; Address; Age; Anatomy; Axon; Behavioral; Biological; Biological Models; Biology; Caring; Central Nervous System; Cervical spinal cord injury; Cervical spinal cord structure; Chronic; Clinical; Complement; Corticospinal Tracts; Data; Development; Disease; Forelimb; Foundations; Funding; Goals; Grant; Growth; Health; Healthcare Systems; Histology; Human; Individual; Injury; Intervention; Laboratory mice; Longevity; Modeling; Molecular; Mus; Natural regeneration; Nature; Neurologic; Neurons; Paralysed; Pathway interactions; Pattern; Persons; Phase; Publishing; Quality of life; Recovery; Recovery of Function; Rehabilitation therapy; Reporting; Research; Side; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Stroke; Synapses; Testing; Three-Dimensional Imaging; Time; Training; Trauma; Traumatic Brain Injury; Veterans; age effect; axon growth; axon regeneration; axonal sprouting; central nervous system injury; experimental study; functional improvement; gene discovery; improved; injured; model organism; mouse model; nonhuman primate; repair strategy; repaired; restorative treatment; skills; synergism; therapeutic development

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.

VA每年治疗超过26，000名脊髓损伤（SCI）和疾病患者， 该部门是世界上最大的医疗保健系统，提供脊髓护理。更好地了解 中枢神经系统（CNS）损伤后的轴突修复对于恢复性治疗的发展至关重要 对于SCI患者，尤其是慢性受伤者。本提案的首要目标是了解 轴突发芽是中枢神经系统内源性修复机制的一种形式，如何增强和利用 促进慢性SCI的功能恢复。这项研究的一个重要前提是， 从未受损伤的神经元发芽代表了轴突修复的一种重要且容易获得的形式， 与更具挑战性的再生促进相比， 战略布局以往的研究主要集中在脊髓损伤的急性期或亚急性期。当前 资助机制将鼓励我们深入研究慢性损伤轴突发芽的重要生物学。 这项建议建立在我们最近发表的关于年龄对CNS轴突再生的影响的研究基础上， 我们未发表的关于年龄和慢性损伤对轴突修复影响的初步数据。使用鼠标 皮质脊髓束（CST）作为模型系统，我们将测试的假设，发芽可以发生， 有助于慢性SCI的功能恢复，并且这种内源性修复机制可以增强 通过分子干预治疗慢性损伤的中枢神经系统。我们将采用单侧正中神经切断损伤模型 切断一侧的CST，研究从中线到失神经侧的发芽。我们将评估 慢性损伤小鼠中CST轴突发芽的水平，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。我们还将结合联合收割机的萌芽促进战略， 康复训练，以促进慢性脊髓损伤后的功能恢复。在一起，拟议的 研究将探讨轴突发芽作为一种潜在的更容易获得的修复机制的潜力， 促进慢性SCI功能恢复。

项目成果

Targeting PTEN but not SOCS3 resists an age-dependent decline in promoting axon sprouting.

靶向PTEN，但不是SOCS3，可以抵抗促进轴突发芽的年龄依赖性下降。

• DOI: 10.1016/j.isci.2022.105383
• 发表时间: 2022-11-18
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Geoffroy, Cedric G.;Meves, Jessica M.;Kim, Hugo Jae Mun;Romaus-Sanjurjo, Daniel;Sutherland, Theresa C.;Li, Jeffrey J.;Suen, Juliet;Sanchez, Joshua J.;Zheng, Binhai
• 通讯作者: Zheng, Binhai

Overexpressing eukaryotic elongation factor 1 alpha (eEF1A) proteins to promote corticospinal axon repair after injury.

过表达的真核伸长因子1α（EEF1A）蛋白可在受伤后促进皮质脊髓轴突修复。

• DOI: 10.1038/s41420-022-01186-z
• 发表时间: 2022-09-20
• 期刊: CELL DEATH DISCOVERY
• 影响因子: 7
• 作者: Romaus-Sanjurjo, Daniel;Saikia, Junmi M.;Kim, Hugo J.;Tsai, Kristen M.;Le, Geneva Q.;Zheng, Binhai
• 通讯作者: Zheng, Binhai

Understanding the axonal response to injury by in vivo imaging in the mouse spinal cord: A tale of two branches.

通过小鼠脊髓体内成像了解轴突对损伤的反应：两个分支的故事。

• DOI: 10.1016/j.expneurol.2019.04.008
• 发表时间: 2019
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Zheng,Binhai;Lorenzana,ArianaO;Ma,Le
• 通讯作者: Ma,Le