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

锌是中枢神经系统损伤后细胞死亡和轴突再生的关键调节剂

• 批准号: 8976844
• 负责人: LARRY Ira BENOWITZ
• 金额: $ 56.42万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-02 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976844
• 关键词: Adult; Afferent Neurons; Apoptosis; Axon; Binding; Biological Models; Caspase; Cell Death; Cell Nucleus; Cell Survival; Cell membrane; Cells; Cessation of life; Chelating Agents; Clinical; Crush Injury; Data; Dendrites; Down-Regulation; Dyes; Event; Eye; Failure; Family member; Genes; Goals; Growth; HDAC3 gene; HDAC5 gene; Health; Histone Acetylation; Histone Deacetylation; Histones; Hour; In Vitro; Indium; Injury; Inner Plexiform Layer; Intervention; Lead; Mediator of activation protein; Mus; Natural regeneration; Nerve; Nerve Crush; Nerve Regeneration; Nervous System Trauma; Nervous system structure; Neuraxis; Neuronal Injury; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Nuclear; Optic Nerve; Optic Nerve Injuries; Pathway interactions; Patients; Peripheral; Play; Potassium Channel; Process; Production; Proteins; Publishing; Recovery; Recovery of Function; Regulation; Reporting; Retina; Retinal Ganglion Cells; Role; Signal Transduction; Spinal cord injury; Stress; Stroke; Synapses; Synaptic Transmission; System; Testing; Time; Transferase; Up-Regulation; Work; Zinc; analog; axon growth; axon injury; axon regeneration; base; central nervous system injury; channel blockers; chelation; chemical genetics; extracellular; functional restoration; genetic approach; immunocytochemistry; improved; improved outcome; in vivo; inhibitor/antagonist; injured; nerve injury; neuron loss; neuronal cell body; presynaptic; prevent; programs; regenerative; response; synaptic function; trafficking

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.

描述（由申请人提供）：锌已被证明对突触传递具有多种重要和独特的作用，并被认为是神经元损伤的关键介质。我们现在已经发现了一个以前未被认识到的作用，锌作为一个主要的轴突再生和细胞存活的抑制轴突损伤后，在中枢神经系统（CNS）。在正常情况下，成年CNS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能发生的恢复量。视神经是中枢神经系统（CNS）的组成部分，由于其可及性、解剖简单性和功能重要性，已被广泛用于研究CNS再生。虽然眼睛的投射神经元，视网膜神经节细胞（RGC），通常不能再生损伤的轴突，但这种不能在小鼠中通过激活RGC的内在神经元的治疗可以部分逆转。 生长状态和抵消轴突生长的细胞外源性抑制剂。然而，这些操作仅导致有限的再生，这表明我们目前对调节CNS中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6小时内，视网膜的内丛状层（IPL）中的Zn 2+显著升高，所述内丛状层（IPL）包含从无长突细胞和双极细胞到RGC树突的突触接触。这种增加代表视神经损伤后的非常早期事件。在接下来的几天里，Zn 2+在RGC胞体中积累。重要的是，螯合细胞外Zn 2+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产生显著影响。因此，我们假设，锌是一个主要的抑制剂的再生潜力的轴突神经损伤后，以及神经元死亡的原因。具体目标是：1）表征视神经挤压后Zn 2+积累的时间、定位和机制; 2）确定Zn 2+是否通过组蛋白脱乙酰酶调节轴突再生;和3）表征Zn 2+抑制和螯合增强RGC存活的途径。这些研究将大大增加我们对锌在正常和受损神经系统中所起作用的理解，并可能导致治疗，以帮助改善CNS损伤后的结果。