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: 8623157
• 负责人: YIMIN ZOU
• 金额: $ 19.18万
• 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/8623157
• 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）：中枢神经系统中的轴突在创伤性损伤后不容易再生，因为成人的高度抑制环境 中枢神经系统，尤其是在受伤后。此外，成年轴突通常缺乏内在的生长潜力，因此不能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，受损的轴突往往会从受损的地方进一步缩回，使修复更具挑战性。因此，组合的方法将是必要的成功的解剖再生和功能恢复。许多在发育中重要的轴突导向分子在神经系统之后仍然存在于成人中枢神经系统中。还有一些是在受伤后重新诱发的。Wnt是一种引导信号，它控制着发育中的脊髓头尾轴上沿着的一些轴突的寻路。Wnt通过其七跨膜受体Frizzleds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，再诱导的Wnt信号系统调节损伤的成年中枢神经系统轴突的生长锥。Ryk介导的Wnt排斥引起损伤的皮质脊髓束轴突的众所周知的回缩/回死，并且限制本体感受感觉轴突的再生潜力，即使在它们的外周分支的条件性损伤之后，由此压碎外周分支增强感觉轴突的中央分支的生长状态。该补助金测试是否可以通过组合方法进行更有效的再生。我们将测试结合Wnt信号传导操纵和PTEN缺失是否可以进一步增强条件损伤的再生潜力。