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而独特的影响，并被认为是神经元损伤的关键介质。我们现在已经发现了锌在中枢神经系统（CNS）轴突损伤后作为轴突再生和细胞存活的主要抑制因子的先前未被认识的作用。在正常情况下，成人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、中风和其他类型神经损伤后的恢复能力。视神经是中枢神经系统（CNS）的一个组成部分，由于其可及性、解剖简单性和功能重要性，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（RGCs）通常不能再生受损的轴突，但在小鼠中，通过激活RGCs固有的治疗可以部分逆转这种无能

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.