Zinc is a critical regulator of cell death and axon regeneration after CNS injury

描述(由申请人提供)：锌已被证明对突触传递有多种重要和独特的影响，并被认为是神经元损伤的关键介质。我们现在发现，在中枢神经系统(CNS)轴突损伤后，锌作为轴突再生和细胞存活的主要抑制因子的作用之前并不为人所知。在正常情况下，成年中枢神经系统中的神经元不能再生受损的轴突，这严重限制了脊髓损伤、中风和其他类型的神经损伤后可以发生的恢复量。视神经是中枢神经系统(CNS)的重要组成部分，因其易获得性、解剖结构简单和功能重要性而被广泛用于研究中枢神经系统的再生。虽然眼睛的投射神经元，即视网膜神经节细胞(RGC)，通常不能再生受损的轴突，但这种能力可以通过激活RGCs固有的治疗在小鼠身上部分逆转。 生长状态和对抗细胞外源性轴突生长抑制因子。然而，这些操作只能导致有限的再生，这表明我们目前对调节中枢神经系统神经元再生潜力的因素的理解是不完整的。我们的初步数据显示，在视神经损伤后的6小时内，视网膜内网状层(IPL)中的锌离子急剧增加，该层包含从无长突细胞和双极细胞到视网膜节细胞树突的突触接触。这种增加是视神经损伤后的一个非常早期的事件。在接下来的几天里，锌离子在RGC体细胞中积累。重要的是，螯合细胞外锌离子的试剂提供了持久的保护，防止RGC死亡，并对这些细胞通过视神经再生受损轴突的能力有显著影响。因此，我们推测，锌离子是神经损伤后轴突再生潜力的主要抑制者，也是神经元死亡的原因之一。本研究的具体目的是：1)研究视神经损伤后锌离子蓄积的时间、定位和机制；2)确定锌离子是否通过组蛋白脱乙酰酶调节轴突再生；3)研究锌离子抑制和络合促进RGC存活的途径。这些研究将极大地帮助我们了解锌在正常和受损神经系统中所起的作用，并可能导致治疗方法，以帮助改善中枢神经系统损伤后的预后。

DESCRIPTION (provided by applicant): Zinc has been shown to have multiple important and distinct effects on synaptic transmission and has been implicated as a critical mediator of neuronal injury. We have now discovered a previously unrecognized role for zinc as a major suppressor of axon regeneration and cell survival following axonal injury in the central nervous system (CNS). Under normal conditions, neurons in the adult CNS cannot regenerate damaged axons, placing severe limitations on the amount of recovery that can occur after spinal cord injury, stroke, and other types of neurological damage. The optic nerve is an integral part of the central nervous system (CNS) that has been widely used to investigate CNS regeneration due to its accessibility, anatomical simplicity, and functional importance. Although the projection neurons of the eye, the retinal ganglion cells (RGCs), are normally unable to regenerate injured axons, this inability can be partially reversed in mice by treatments that activate RGCs' intrinsic growth state and by counteracting cell-extrinsic inhibitors of axon growth. However, these manipulations result in only limited regeneration, suggesting that our current understanding of the factors that regulate neurons' regenerative potential in the CNS is incomplete. Our preliminary data show that within 6 hours after injuring the optic nerve, there is a dramatic elevation of Zn2+ in the inner plexiform layer (IPL) of the retina, which contains synaptic contacts from amacrine and bipolar cells onto the dendrites of RGCs. This increase represents a very early event following optic nerve damage. Over the next few days, Zn2+ accumulates in RGC somata. Importantly, agents that chelate extracellular Zn2+ provide enduring protection against RGC death and have a dramatic effect on these cells' ability to regenerate injured axons through the optic nerve. We therefore hypothesize that Zn2+ is a major suppressor of the regenerative potential of axons after nerve injury as well as a cause of neuronal death. The specific aims are to: 1) Characterize the timing, localization, and mechanism of Zn2+ accumulation following optic nerve crush; 2) Determine whether Zn2+ regulates axon regeneration via histone deacetylases; and 3) Characterize the pathways by which Zn2+ suppresses, and chelation enhances, RGC survival. These studies will add greatly to our understanding of the role that Zn2+ plays in the normal and injured nervous system, and may lead to treatments to help improve outcome after CNS injury.