GRAFT FUNCTION

对神经生物学后遗症的片段性认识 移植反映在逆转尝试的不同成功程度上 纹状体内胎儿在人类和非人灵长类动物中的帕金森病 组织移植。本项目将调查功能的基础 采用神经化学和形态测量的康复方法及其相关 在灵长类动物模型中移植后的行为恢复 帕金森氏症。这些知识将有助于改进 移植技术。这些研究中使用的模型是同种异体心脏移植。 胎儿腹侧中脑移植到大鼠尾状核内 经MPTP治疗的帕金森病猴子。 拟议中的实验将解决关于改进 胎儿腹侧移植后帕金森综合征的观察 中脑是由于移植物的存在，而移植物- 诱导恢复依赖于多巴胺的存在 嫁接。这些问题将在一项研究中进行审查，该研究涉及 一旦改善，移植组织的免疫排斥反应 发生了。如果经济复苏被发现严重依赖于 移植物的存在，我们将调查多巴胺对 通过破坏移植物中的多巴胺神经元来改善。 其他研究将调查a)改善的程度是否 依赖于尾状核多巴胺能恢复的程度， 以及需要多少神经再支配，b)多巴胺能 神经再生会随着时间的推移而变化，如果这种变化与 帕金森氏症的改变，以及c)多巴胺能神经重新支配 可通过胎儿或成人纹状体的联合移植来增强 外周神经来源的雪旺细胞，如果是这样，如果它对应于 减少帕金森症患者的行为。这些实验将利用 定量多巴胺转运体放射自显影，多巴胺浓度， 高香草酸与多巴胺的比值和酪氨酸羟基酶 免疫组织化学。 进一步的实验将确定移植的多巴胺神经元 用GABA能和胆碱能建立正常突触联系 宿主尾状核中的神经元。这将通过以下方式解决 双重免疫染色切片的相关光镜和电子显微镜观察 从尾状核的一个明确的区域，非常接近 嫁接。 这些研究将进一步深入了解移植的基础-- 诱导帕金森症患者的行为恢复。这些措施的结果 调查将在量身定做研究和 神经退行性疾病的未来治疗。

The fragmentary understanding of the biological sequelae of neural transplantation is reflected in the variable success of attempts to reverse parkinsonism in human and non-human primates using intrastriatal fetal tissue grafts. This project will investigate the basis of functional recovery employing neurochemical and morphological measures and relating them to behavioral recovery following grafting in a primate model of parkinson's disease. This knowledge will facilitate refinement of the transplantation technique. The model used in these studies is allograft of fetal ventral mesencephalon transplanted into the caudate nucleus of the MPTP-treated parkinsonian monkey. The proposed experiments will address the controversy that the improvement in parkinsonism observed following transplantation of fetal ventral mesencephalon is due to the presence of the graft and that the graft- induced recovery is dependent on the presence of dopamine derived from the graft. These issues will be examined in a study that involves immunological rejection of the grafted tissue, once the improvement has occurred. If the recovery is found to be significantly dependent on the presence of the graft, we will investigate the dopamine-dependence of the improvement by destruction of the dopamine neurons in the graft. Other studies will investigate a) whether athe extent of improvement is dependent on the degree of dopaminergic restoration of the caudate nucleus, and how much reinnervation is necessary, b) whether the dopaminergic reinnervation changes with time and if this change is paralleled by alterations in parkinsonism, and c) whether the dopaminergic reinnervation can be enhanced by the presence of co-grafts of fetal striatum or adult peripheral nerve-derived Schwann cells, and if so, if it corresponds to decreased parkinsonian behavior. These experiments will utilize quantitative dopamine transporter autoradiography, dopamine concentrations, homovanillic acid to dopamine ratios and tyrosine hydroxylase immunohistochemistry. Further experiments will determine whether the grafted dopamine neurons establish normal synaptic connections with GABAergic and cholinergic neurons in the host caudate nucleus. This will be addressed using correlated light and electron microscopy of double-immunostained sections from a defined region of the caudate nucleus in close proximity to the grafts. These studies will provide further insight into the basis of transplant- induced behavioral recovery from parkinsonism. The outcome of these investigations will have an important impact in tailoring research and future treatments of neurodegenerative disorders.