IN VITRO TESTS OF ACUTE SCI TREATMENT STRATEGIES

急性 SCI 治疗策略的体外测试

• 批准号: 2267812
• 负责人: JEN H LUCAS
• 金额: $ 23.75万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2267812
• 关键词: alternatives to animals in research; apoptosis; cell death; electrophysiology; gangliosides; laboratory mouse; methylprednisolone; nervous system regeneration; neurons; neuroprotectants; nonhuman therapy evaluation; protein biosynthesis; spinal cord injury; tissue /cell culture

The proposed investigations continue a research effort that began in 1983 and has been supported by three grants from the NIH. A tissue culture model of nerve cell injury where techniques of laser cell surgery were used to effect neurite transection lesions in individual mammalian spinal cord (SC) neurons was used to evaluate treatment strategies for the physical (membrane disruption) trauma of acute phase spinal cord injury (SCI). A central goal has been to demonstrate the potential of the in vitro investigative approach for the study of questions relevant to in vivo CNS trauma. Three observations made in the course of these evaluations form the basis for the continuation proposal: (1) that inhibition of protein synthesis increases survival of lesioned neurons from approximately 50% to 80%, (2) that barbiturates increase survival from 50% to 70%, and (3) that controlled cooling (17 degrees C for 2h) increases survival from 50% to 70%. The significant protection by these interventions is in contrast to the modest protection of lesioned neurons by methylprednisolone (Rosenberg-Schaffer and Lucas, 1993) which is currently the treatment modality of choice for SCI. The first set of specific aims (Section I) will test three hypotheses: (1) that a significant proportion of the neuronal death that occurs after neurite transection is a type of "programmed" cell death, (2) that survival or death is correlated with the synthesis of specific messenger RNA's and/or proteins associated with injury and morbidity, and (3) that residual electrical activity contributes to death after dendrotomy. The last aim (Section II) to perform an extensive dose-response evaluation of the ability of GM1 ganglioside to protect neurons after dendrotomy, continues our in vitro evaluations of promising, experimental clinical treatments for acute phase SCI. Because GM1 has been reported to abolish protection by methylprednisolone, we will also compare the combination of GM1 and methylprednisolone to the individual treatments. The first set of specific aims will provide information about the molecular mechanisms underlying traumatic neuronal death, and may elucidate new strategies for the treatment of acute phase SCI. Fulfillment of the last specific aim will provide much-needed information relevant to the efficacy of GM1 as an acute phase treatment for the primary mechanical trauma of SCI, the optimum "dosage" and time for initiation of treatment, and the efficacy of GM1 combined with methylprednisolone. The combined expertise of the members of the research team will be utilized for the systematic survival, ultrastructural, molecular, and electrophysiological evaluations required for fulfillment of the specific aims.

拟议的调查继续进行研究，从1983年开始 并得到了NIH的三项赠款的支持。组织培养 激光细胞手术技术的神经细胞损伤模型 用于在单个哺乳动物脊柱中影响神经突式损伤 电线（SC）神经元用于评估治疗策略 急性期脊髓损伤的物理（膜破坏）创伤 （SCI）。一个中心目标是证明IN的潜力 研究与In相关问题的研究方法 Vivo CNS创伤。 在这些评估过程中进行的三个观察结果构成了基础 对于持续建议：（1）抑制蛋白质合成 病变神经元的存活率从约50％增加到80％，（2） 巴比妥类药物将生存率从50％增加到70％，（3） 受控冷却（2H摄氏度为17度）将存活率从50％增加到 70％。这些干预措施的重大保护与 甲基促旋龙对病变神经元的适度保护 （Rosenberg-Schaffer和Lucas，1993）目前是治疗 SCI的首选方式。第一组特定目的（第I节） 将检验三个假设：（1）很大一部分 神经突术后发生的神经元死亡是一种 “编程”细胞死亡，（2）生存或死亡与 与特定信使RNA和/或蛋白质的合成 伤害和发病率，以及（3）残留电活动 树突切开后死亡。 最后一个目标（第二节） 对GM1的能力进行广泛的剂量反应评估 神经节苷脂在树突切开术后保护神经元，继续我们的体外 评估急性期有希望的实验临床治疗 科学。 因为已报告GM1被据报道废除保护 甲基强酮，我们还将比较GM1和 甲基促进性的甲硅酮。 第一组特定目标将提供有关 神经元死亡的分子机制，可能 阐明治疗急性科学的新策略。履行 最后的特定目的将提供与 GM1作为主要机械的急性相处理的功效 SCI的创伤，最佳的“剂量”和开始治疗的时间， GM1的功效与甲基促旋甲硅酮相结合。组合 研究小组成员的专业知识将用于 系统生存，超微结构，分子和电生理学 实现特定目标所需的评估。