EARLY MOLECULAR EVENTS IN THE RESPONSE TO AXON INJURY

轴突损伤反应中的早期分子事件

• 批准号: 3418249
• 负责人: DANIEL J GOLDBERG
• 金额: $ 17.51万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-01 至 1995-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3418249
• 关键词: axon; gel mobility shift assay; neural degeneration; transcription factor

Axon injury is, unfortunately, common and of enormous consequence to public health. For example, the paralysis pursuant to trauma to the spinal cord is a direct result of the interruption of axons running longitudinally in the cord; the inability of these axons to regenerate renders the paralysis effectively permanent. The cell body from which a transected axon arises displays electrical and biochemical changes in response to the injury that underlie degenerative, protective and regenerative responses of the cell, since it is in the cell body that the proteins for the neuron are manufactured. The work in this project seeks to help define the molecular events occurring in the cell body that underlie the response to axotomy. The work will focus on early events in the nucleus that could trigger or orchestrate subsequent degenerative, protective or regenerative responses. Preliminary screening experiments using a giant invertebrate neuron have detected a few nuclear proteins which respond rapidly and particularly strongly to axotomy. One of these may be a known gene-regulatory protein, CREB. Work in this project is designed to follow up this lead by confirming the identification of CREB and determining whether a related gene-regulatory factor (AP-1) also responds to axotomy and determining the mode of regulation of CREB. Also, through the use of a technique that blocks the functioning of CREB or AP-1, it will be determined whether CREB or AP-1 functioning is necessary for certain important responses of the neuron to axotomy, such as the overall increase in protein and RNA synthesis or the increase in production of specific proteins involved in growth. The knockout technique capitalizes on the enormous size of certain Aplysia neurons. Work is also designed to determine whether mammalian peripheral and/or central neurons display an early CREB response and whether the response is correlated with the regenerative potential of the neuron.

不幸的是，轴突损伤很常见，并且对人体造成巨大后果 公共卫生。 例如，因外伤而导致的瘫痪 脊髓是轴突运行中断的直接结果 沿绳索纵向；这些轴突无法再生 使瘫痪有效地永久化。 细胞体来自于 横断的轴突出现，显示出电学和生化变化 对退化性、保护性和保护性损伤的反应 细胞的再生反应，因为细胞体是在细胞体内进行的 神经元的蛋白质被制造出来。 该项目的工作旨在 帮助定义细胞体内发生的分子事件 是对轴切术反应的基础。 这项工作将集中于早期事件 在可能触发或协调随后退化的细胞核中， 保护性或再生性反应。 初步筛选实验 使用巨大的无脊椎动物神经元检测到一些核蛋白 对轴突切除术反应迅速且特别强烈。 其中之一 可能是已知的基因调节蛋白CREB。 该项目的工作是 旨在通过确认 CREB ​​的身份来跟进这一线索 并确定相关基因调节因子（AP-1）是否也 响应轴索切断术并确定 CREB ​​的调节模式。 此外，通过使用阻止 CREB ​​功能的技术 或 AP-1，将确定 CREB ​​或 AP-1 功能是否正常 神经元对轴切术的某些重要反应是必需的，例如 随着蛋白质和RNA合成的总体增加或 产生与生长有关的特定蛋白质。 淘汰赛 该技术利用了某些海兔神经元的巨大尺寸。 工作还旨在确定哺乳动物的外周和/或 中枢神经元表现出早期 CREB ​​反应，以及该反应是否 与神经元的再生潜力相关。