Combinatorial approaches to maximize axon regeneration after spinal cord injury

脊髓损伤后最大化轴突再生的组合方法

• 批准号: 8556666
• 负责人: YIMIN ZOU
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8556666
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Afferent Neurons; Alleles; Antibodies; Axon; Back; Behavior assessment; Biological Assay; Cicatrix; Contusions; Corticospinal Tracts; Cues; Demyelinations; Development; Dorsal; Environment; Exhibits; Failure; Family; Fiber; Forelimb; Genetic; Grant; Growth; Growth Cones; Inflammatory Response; Infusion procedures; Injury; Knock-out; Lesion; Link; Mediating; Methods; Modeling; Monoclonal Antibodies; Motor; Myelin; Natural regeneration; Nerve Crush; Nerve Regeneration; Nervous system structure; Neuraxis; Neurons; PTEN gene; Patients; Peripheral; Property; Publications; Recovery; Recovery of Function; Research; Sensory; Signal Transduction; Site; Spinal Cord; Spinal cord injury; System; Testing; Therapeutic; Time; axon growth; axon guidance; axon regeneration; base; combinatorial; conditioning; design; efficacy testing; gray matter; improved; inhibitor/antagonist; injured; neuronal survival; novel; public health relevance; receptor; regenerative; repaired; white matter

DESCRIPTION (provided by applicant): Axons in the central nervous system do not regenerate readily after traumatic injury because of the highly inhibitory environment of the adult central nervous system especially following injury. In addition, adult axons generally lack intrinsic growth potential and therefore cannot sustain the initial sprouting observed in some of the injured axons. Furthermore, injured axons often retract further back from where they are lesioned over time, making repair even more challenging. Therefore, combinatorial approaches will be necessary for successful anatomical regeneration and functional recovery. Many axon guidance molecules important in development are still present in the adult central nervous system after the nervous system. Still others are found re- induced after injury. Wnts are guidance cues that control pathfinding of a number of axons along the rostral-caudal axis of the developing spinal cord. Wnts attract ascending axons via their seven-span transmembrane receptors, Frizzleds, and repel others via a different transmembrane receptor, Ryk, in the spinal cord. Our studies showed that the re-induced Wnt signaling system regulates the growth cone of axons in the injured adult central nervous system. Ryk-mediated Wnt repulsion causes the well-known retraction/die back of injured corticospinal tract axons and limits the regenerative potential of proprioceptive sensory axons even after conditioning lesion of their peripheral branches, whereby crushing the peripheral branch enhances the growth state of the central branch of sensory axons. This grant tests whether more effective regeneration can occur by combinatorial approaches. We will test whether combining Wnt signaling manipulation and PTEN deletion can further enhance the regenerative potential of conditioning lesion.

描述（由申请人提供）：由于成人的高度抑制环境，中枢神经系统中的轴突不容易再生 中枢神经系统，尤其是受伤后。此外，成年轴突通常缺乏内在的生长潜力，因此无法维持某些受伤的轴突中观察到的最初发芽。此外，受伤的轴突经常从随着时间的流逝而恢复后的轴突，从而使修复更具挑战性。因此，组合方法对于成功的解剖学再生和功能恢复是必要的。神经系统之后，成人中枢神经系统中仍然存在许多重要发育中的轴突引导分子。还有其他人在受伤后诱发。 WNT是指导线索，可控制发育中脊髓的尾auda轴轴突的许多轴突。 Wnt通过其七跨膜跨膜受体，卷曲和通过不同的跨膜受体Ryk在脊髓中吸引轴突。我们的研究表明，重新诱导的WNT信号系统调节受伤的成年中枢神经系统中轴突的生长锥。 RYK介导的WNT排斥力导致众所周知的缩回/死亡皮层脊髓轴突的后部，即使在调节外围分支的病变后，也限制了本体感受性感觉轴突的再生潜力，从而粉碎了外围分支，从而增强了感觉轴突中央分支的生长状态。该赠款测试是否可以通过组合方法发生更有效的再生。我们将测试WNT信号操纵和PTEN缺失是否可以进一步增强调节病变的再生潜力。