FETAL DOPAMINE CELLS--IMPROVING GRAFT VIABILITY

应用神经网络最大的困难之一 移植治疗神经退行性疾病 提高移植供体组织的存活率，以确保足够的 会产生大量的多巴胺，移植效果是长期的- 经久不衰。一家著名的实验室报告称， 按照目前的技术，移植的人类多巴胺神经元的比例低至2%-5%， 在啮齿动物身上进行了测试。该实验室和其他实验室使用了这一结论 显著增加植入人体的组织数量的基础 临床实验。 我们已经能够实现相当高的存活率 灵长类动物通过研究可能增强它的因素。提高患者的存活率 移植可以从从关键阶段获得的组织中获得 多巴胺神经发生。值得注意的是，临床实验已经 使用的孕周范围比所建议的要大得多 来自我们的新数据。此外，我们发现，长期实施的 在啮齿动物中左旋多巴导致移植的多巴胺神经元发育迟缓和 行为改善减弱。与此相关的其他因素 供体组织或药物治疗的制备和储存 嫁接后可能同样重要。尽管一些研究进行了 在老鼠身上可能提供有用的线索，据了解，更大的尺寸和 猴脑的复杂性及其与人脑的相似性使 在猴模型中优化移植物的生存能力是至关重要的。 需要研究的变量包括供体组织的年龄、移植物存活率 随着时间的推移，制备细胞等供体组织的方法 悬浮液、固体移植物和冷冻保存，以及 传统药物疗法，如左旋多巴、扑热息痛等 移植物存活率。这些研究将使用移植的 在几个时间段内将中脑组织转化为猴子，控制 就胎龄而言，悬浮与小型固体移植物的配对比较 植入同一只猴子尾状核的两侧， 新鲜和冷冻保存的组织也被植入到 大脑。药理学研究将首先在灵长类细胞培养中进行 如果是阳性的，后续的实验将测试这些对移植的影响 猴子。 该项目还将检验胚胎移植的有效性。 纹状体促进移植中脑神经突起生长的实验研究 作为一种从移植的神经元中获得更大突起的手段。在.期间 目前获奖期间，我们还发现纹状体移植物有生长 对宿主大脑的增强作用，可导致生长 酪氨酸羟化酶阳性纤维植入移植物内 背外侧纹状体。我们将从以下角度来审视这一现象 旨在保护残存宿主的早期干预的前景 多巴胺能神经元。

One of the foremost difficulties with the application of neural transplantation to the treatment of neurodegenerative disorders is enhancing the survival of grafted donor tissue to ensure that adequate amounts of dopamine are produced and that transplant effect are long- lasting. One prominent laboratory reported that the survival rate of grafted, human dopamine neurons is as low as 2-5% using current techniques, tested in rodents. This laboratory and others have used this conclusion as the basis for substantially increasing the amount of tissue implanted in clinical experiments. We have been able to achieve a considerably higher survival rate in primates by studying factors which might enhance it. Improved survival of grafts may be achieved from tissue obtained from a critical stage of dopamine neurogenesis. It may be noteworthy that clinical experiments have utilized a much wider range of gestational ages than would be suggested from our new data. Moreover, we have found that chronically administered levodopa in rodents results in grafts with stunted dopamine neurons and diminished behavioral improvement. Other factors related to the preparation and storage of the donor tissue or pharmacological treatments after grafting may be equally important. Although some studies performed in rat may provide useful clues, it is understood that the greater size and complexity of the monkey brain and its similarity to the human brain makes it essential to optimize the viability of grafts in monkey models. Variables to be studied include the age of the donor tissue, graft survival over time, the method of preparation of the donor tissue such as cell suspension, solid grafts, and cryopreservation, and the effects of conventional pharmacotherapies such as levodopa, deprenyl and others on graft survival. These studies will be carried out using grafts of mesencephalic tissue into monkeys over several time periods, controlling for fetal age, matched comparisons of suspended vs. small solid grafts implanted on opposite sides of the caudate nucleus of the same monkey, fresh vs. cryopreserved tissue also implanted on opposite sides of the brain. Pharmacological studies will be done first in primate cell cultures and, if positive, subsequent experiments will test these effects on grafted monkeys. This project also will examine the effectiveness of grafts of embryonic striatum to promote growth of neurites from co-grafted mesencephalic tissue as a means of achieving greater outgrowth from grafted neurons. During the current award period we also discovered that striatal grafts have a growth enhancing effect on the host brain that can result int he growth of tyrosine hydroxylase positive fibers into grafts placed into the dorsolateral striatum. We will examine this phenomenon from the perspective of early intervention designed at protecting the residual host dopaminergic neurons.