GLIAL CELL TRANSPLANTATION AND CNS REMYELINATION

描述：(改编自申请者摘要)：此为重新提交 上一次审查该提案是在1994年10月。建议的主题 研究目的是开发神经胶质细胞移植的动物模型 遗传性或获得性脱髓鞘疾病。总体目标是 确定产生全局性中央髓鞘再生的可行性 神经系统(CNS)。测试的策略将涉及新生儿和 成人，包括炎症的存在和影响的一些情景 和神经胶质增多症。实验结果将由组织学监测 重新获得正常的髓鞘含量和功能 电生理评估。报告中引用的主要批评 先前的审查涉及到对 调查，因为它与许多实验动物模型有关 脱髓鞘，而不是对一两个进行更深入的分析 模特们。此外，前一次审查指出，明显缺乏明显的 与已经完成的工作有关的拟议延期和 缺乏可能被认为更直接地与 人类疾病。此外，调查人员被建议将重点放在 实验结果更多地是关于神经元电导的恢复，而不是 比核磁共振分析，这应该允许更直接的评估相关 对神经传递的生理影响。针对上一次 评论中，邓肯博士提供了更多关于 他计划使用的每个实验模型，其中一些是 最近的出版物。他删除了大部分涉及核磁共振的分析， 现在支持上一篇综述所建议的电导研究。 虽然异体移植很少受到重视，但更多的是强调 将被放在成人移植上，使研究更多 与各种人类场景相关。因此，该计划的具体目标是 建议有：具体目标1：示范移植传播 细胞和大规模的再髓鞘形成。生产的可行性 移植细胞通过脑室的广泛扩散 系统和随后对神经纤维的侵入将通过注射进行测试 少突胶质细胞前体细胞进入成人、新生儿侧脑室的实验研究 和胚胎突变大鼠。此外，这将在一个长期的 实验性变态反应性脑脊髓炎模型。细胞的传播 也将尝试通过脊髓蛛网膜下腔进行手术。 连续脊髓节段内多焦点注射相似细胞 将进行检查以确定是否存在连续的髓鞘再生 可以沿着几个脊髓节段延伸。 具体目标2：确定炎症和胶质细胞增生症是否抑制或 通过移植神经胶质细胞防止再髓鞘形成。动物模型，其中 炎症和/或慢性胶质细胞增生症突出者可作为 移植神经胶质细胞的受体及其迁移和髓鞘形成 将确定病变区域内和通过病变区的移植细胞。 例如，在将要使用的慢性EAE模型中，局灶性植入 细胞将被用来检查这些细胞是否会通过 正常神经纤维层向局灶性脱髓鞘斑块发展。此外, 移植到慢性脱髓鞘区域有望确定 在长时间的脑缺血后轴突能否成功地重新髓鞘形成 非包裹性。 特定目标3：确定神经胶质细胞的功能效应 移植。新生儿和成人的神经胶质细胞移植 脱髓鞘突变体之后将进行生理功能测试。 这将是耶鲁大学邓肯博士和科西斯博士之间的合作 大学，谁将进行电生理测量。

DESCRIPTION: (Adapted from Applicant's Abstract): This is a re-submission of a proposal last reviewed in October of 1994. The theme of the proposed studies is to develop glial cell transplant strategies in animal models of inherited or acquired demyelinating diseases. The overall goal is to determine the feasibility for producing global remyelination of the central nervous system (CNS). Strategies to be tested will involve neonates and adults, some scenarios including the presence and effects of inflammation and gliosis. Experimental outcome is to be monitored histologically by re-acquisition of normal myelin content and functionally by electrophysiological assessments. The primary criticisms cited in the previous review involved concerns over the diffuse nature of the investigation as it pertained to numerous experimental animal models of demyelination, as opposed to performing more in-depth analyses of one or two models. In addition, the previous review cited an apparent lack of obvious extension that was proposed in relation to work already accomplished and a lack of experimentation that might be considered more directly relevant to human disease. Moreover, the investigators were advised to focus experimental outcome more on the restoration of neuronal conductance, rather than MRI analyses, which should allow a more direct assessment of relevant physiological effects on neurotransmission. In response to the previous critique, Dr. Duncan has provided more information concerning the value of each experimental model with which he plans to work, some in the form of recent publications. He has removed the majority of analyses involving MRI, now favoring electric conductance studies as suggested by the last review. Although little attention is to be paid to allo-engraftment, more emphasis is to be placed on adult transplantation, making the studies somewhat more relevant to various human scenarios. Thus, the Specific Aims of the proposal are: Specific Aim 1: Demonstrate dissemination of transplanted cells and large-scale remyelination. The feasibility of producing widespread dissemination of transplanted cells through the ventricular system and subsequent invasion of the neuropil will be tested by injecting oligodendrocyte progenitors into the lateral ventricle of adult, neonatal and fetal mutant rats. In addition, this will be carried out in a chronic experimental allergic encephalomyelitis (EAE) model. Dissemination of cells will also be attempted via the sub-arachnoid space of the spinal cord. Multifocal injection of similar cells into contiguous spinal cord segments will be performed to determine whether a continuous column of remyelination extending along several spinal cord segments can be achieved. Specific Aim 2: Determine whether inflammation and gliosis inhibit or prevent remyelination by transplanted glial cells. Animal models in which inflammation and/or chronic gliosis are prominent are to be used as recipients of transplanted glia, and the migration and myelination by the transplanted cells in and through pathological areas will be determined. For example, in the chronic EAE model to be used, focal implantation of cells will be used to examine whether such cells will migrate through a normal neuropil towards focally demyelinated plaques. In addition, transplantation into areas of chronic demyelination is hoped to determine whether axons can be successfully remyelinated after prolonged periods of non-ensheathment. Specific Aim 3: Determine the functional effect of glial cell transplantation. Glial cell transplantation in neonatal and adult demyelination mutants is to be followed by tests of physiological function. This is to be a collaboration between Dr. Duncan and Dr. Kocsis at Yale University, who will perform the electrophysiological measurements.