MECHANISMS OF NEURONAL DEATH AND NEUROPROTECTION

神经元死亡和神经保护的机制

• 批准号: 6748482
• 负责人: ANTHONY John WINDEBANK
• 金额: $ 17.64万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748482
• 关键词: DNA damage; DNA repair; adduct; apoptosis; biological signal transduction; cell cycle; cis platinum compound; gene targeting; genetically modified animals; laboratory mouse; nerve growth factors; neurons; neuroprotectants; neurotrophic factors; spinal ganglion

DESCRIPTION(Adapted from the Investigator's Abstract): "Mechanisms of Neuronal Death and Neuroprotection" Chemotherapeutic neurotoxins provide model systems in which basic cellular mechanisms relevant to human disease can be studied. Findings can lead directly to design of treatment trials. Neurotoxicity is dose limiting for cis-diamminedichloroplatinum (cisplatin; CDDP), a first line agent for treating ovarian, testicular, and other neoplasms. The primary target is the dorsal root ganglion (DRG) neuron or its axon. We have demonstrated in a rat model that CDDP induces apoptosis in DRG and have replicated this process in vitro. Nerve growth factor (NGF) prevents this cell death. In cancer cells CDDP binds to DNA. Dividing cells respond to DNA damage by slowing or arresting growth allowing the cell to repair damage before proceeding to DNA replication. If DNA damage is extensive, the cell undergoes apoptosis. The investigators have previously demonstrated that CDDP induces apoptosis in neurons. This is preceded by up regulation of nuclear cyclin D1 expression and increased phosphorylation of the retinoblastoma gene product. These biochemical changes and ceil death are prevented by nerve growth factor (NGF). They propose that DNA damage in neurons induces repair processes that up regulate genes associated with transition from G0 to G1. Since it is highly disadvantageous for post-mitotic neurons to divide, they undergo apoptosis. We will test this hypothesis by (1) determining whether CDDP induces DNA damage by forming Pt-DNA adducts in DRG neurons and whether Pt-DNA complexes are sufficient to induce apoptosis; (2) determining which steps in DNA damage recognition or repair are necessary to initiate cisplatin induced neuronal death using mouse knockouts. If they are necessary, do they occur upstream of the cell cycle changes? (3) Determine where NGF interrupts the death pathway and which NGF signal transduction pathway is responsible for rescue. NGF can be used therapeutically as a specific neuroprotectant. It is one of the primary survival factors for DRG neurons, it has been safely administered to humans, systemic NGF has access to DRG neurons in vivo, and most cancer cells do not have NGF receptors. In the future we will determine whether NGF can be used therapeutically in animal and human models of GDDP neurotoxicity. We will also determine whether the effects of NGF are shared by the other DRG growth factors, brain derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3).

描述(改编自调查者摘要)：“神经元的机制 死亡与神经保护“化疗神经毒素提供模型系统 可以研究与人类疾病相关的基本细胞机制。 研究结果可以直接导致治疗试验的设计。神经毒性是剂量 对一线药物顺铂的限量规定 用于治疗卵巢、睾丸和其他肿瘤。主要目标是 背根神经节(DRG)神经元或其轴突。我们已经在一个 顺铂诱导大鼠背根神经节细胞凋亡模型的建立及复制 在试管中。神经生长因子(NGF)可以防止这种细胞死亡。在癌细胞中 CDDP与DNA结合。分裂细胞对DNA损伤的反应是减缓或阻止 生长允许细胞在进行DNA复制之前修复损伤。 如果DNA损伤范围很大，细胞就会发生凋亡。调查人员 已证实CDDP可诱导神经细胞凋亡。这是 在此之前，细胞核周期蛋白D1的表达上调，并增加 视网膜母细胞瘤基因产物的磷酸化。这些生化变化 神经生长因子(NGF)可防止细胞死亡。 他们提出，神经元中的DNA损伤会诱导修复过程 调控与G0向G1过渡相关的基因。因为它是高度的 有丝分裂后的神经元不利于分裂，它们会发生凋亡。我们 我将通过(1)确定CDDP是否通过以下方式导致DNA损伤来检验这一假设 在背根神经节神经元中形成铂-DNA加合物以及铂-DNA复合体是否 足以诱导细胞凋亡；(2)确定DNA损伤的哪些步骤 识别或修复是启动顺铂诱导的神经元所必需的 使用鼠标击倒致死。如果有必要，是否发生在 细胞周期改变？(3)决定NGF在哪里阻断死亡途径 以及哪个NGF信号转导通路负责救援。NGF可以 作为一种特殊的神经保护剂用于治疗。它是最主要的 背根节神经元的存活因子，它已经安全地应用于人类， 系统性NGF可以在体内接触到DRG神经元，而大多数癌细胞不能 有NGF受体。未来我们将确定是否可以使用NGF 在动物和人类GDDP神经毒性模型中的治疗作用。我们还将 确定NGF的影响是否与其他DRG增长共享 因子、脑源性神经营养因子(BDNF)和神经营养因子-3(NT3)。