GLIAL CELL TRANSPLANTATION AND CNS REMYELINATION

描述：（改编自申请人摘要）：这是重新提交的 上次审查是在1994年10月。 建议的主题 研究是在动物模型中开发神经胶质细胞移植策略， 遗传性或获得性脱髓鞘疾病。 总体目标是 确定产生中枢神经系统整体髓鞘再生的可行性， 神经系统（CNS）。 待测试的策略将涉及新生儿和 成人，一些情况，包括炎症的存在和影响 和神经胶质增生。 实验结果将通过以下方法进行组织学监测 重新获得正常的髓鞘含量和功能， 电生理评估。 《世界人权宣言》中引用的主要批评 以前的审查涉及对分散性质的关切， 研究，因为它涉及到许多实验动物模型， 脱髓鞘，而不是进行更深入的分析，一两个 模型 此外，上一次审查提到， 已完成的工作提出的延长建议， 缺乏可能被认为更直接相关的实验， 人类疾病 此外，调查人员被建议将重点放在 实验结果更多的是恢复神经元传导，而不是 比MRI分析，这应该可以更直接地评估相关的 对神经传递的生理影响。 针对此前 评论，邓肯博士提供了更多的信息，有关的价值， 他计划使用的每个实验模型，有些是以 最近的出版物。 他已经删除了大部分涉及MRI的分析， 现在赞成电导的研究，建议由最后审查。 虽然很少注意到异体移植，但更多的是强调 将被放置在成人移植，使研究有点多 与各种人类场景相关。 因此， 具体目标1：展示移植的 细胞和大规模髓鞘再生。 生产的可行性 移植细胞通过心室广泛散布 系统和随后的神经系统入侵将通过注射 少突胶质细胞祖细胞进入成人、新生儿 和胚胎突变鼠 此外，这将在一个长期的 实验性变态反应性脑脊髓炎（EAE）模型。 细胞播散 也将尝试通过脊髓的蛛网膜下腔。 相似细胞多灶性注射入相邻脊髓节段 以确定髓鞘再生的连续柱 可以实现沿着几个脊髓节段延伸。 具体目标2：确定炎症和神经胶质增生是否抑制或 阻止移植的神经胶质细胞的髓鞘再生。 动物模型中， 炎症和/或慢性神经胶质增生是突出的， 移植胶质细胞的受体，以及移植胶质细胞的迁移和髓鞘形成。 将确定病理区域中和通过病理区域的移植细胞。 例如，在待使用的慢性EAE模型中， 细胞将被用来检查这些细胞是否会通过一个 正常神经纤维向局灶性脱髓鞘斑块的方向发展。 此外，本发明还提供了一种方法， 移植到慢性脱髓鞘的区域， 轴突是否能在长时间的 非鞘化。 具体目标3：确定胶质细胞的功能效应 移植 新生儿和成人胶质细胞移植 脱髓鞘突变体之后将进行生理功能测试。 这是耶鲁大学的邓肯博士和科奇斯博士之间的合作 他将进行电生理测量。

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.