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，中枢神经系统的轴突在创伤后不容易再生 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，因此无法维持在一些受损轴突中观察到的初始发芽。此外，随着时间的推移，受伤的轴突通常会从受损位置进一步缩回，使得修复变得更加困难。因此，组合方法对于成功的解剖再生和功能恢复是必要的。许多对发育重要的轴突引导分子在成人中枢神经系统中仍存在于神经系统之后。还有一些人在受伤后会重新出现。 Wnt 是控制沿发育中的脊髓头尾轴的多个轴突寻路的引导信号。 Wnt 通过其七跨跨膜受体 Frizzled 吸引上行轴突，并通过脊髓中不同的跨膜受体 Ryk 排斥其他轴突。我们的研究表明，重新诱导的 Wnt 信号系统可调节受损成人中枢神经系统中轴突的生长锥。 Ryk 介导的 Wnt 排斥会导致众所周知的受损皮质脊髓束轴突的回缩/死亡，并限制本体感觉轴突的再生潜力，即使在其外周分支的调节损伤后也是如此，从而压碎外周分支增强了中央分支的生长状态的感觉轴突。这笔拨款测试是否可以通过组合方法实现更有效的再生。我们将测试结合Wnt信号传导和PTEN缺失是否可以进一步增强调理损伤的再生潜力。