FETAL DOPAMINE CELLS--IMPROVING GRAFT VIABILITY

胎儿多巴胺细胞——提高移植物活力

• 批准号: 6243597
• 负责人: JOHN RICHARD SLADEK
• 金额: $ 19.07万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6243597
• 关键词: Cercopithecidae; Parkinson's disease; brain mapping; cell age; corpus striatum; cryopreservation; cyclosporines; deprenyl; dihydroxyphenylalanine; dopamine; dopamine receptor; electron microscopy; embryo /fetus cell /tissue; gestational age; histochemistry /cytochemistry; methylphenyltetrahydropyridine; nervous system regeneration; nervous system transplantation; neurons; neuropharmacology; neurotoxins; substantia nigra; tissue /cell culture; tyrosine 3 monooxygenase

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.

应用神经网络的最大困难之一是 移植治疗神经变性疾病， 提高移植供体组织的存活率，以确保足够的 大量的多巴胺产生，移植效果是长期的- 持久 一个著名的实验室报告说， 移植的人多巴胺神经元使用现有技术低至2-5%， 在啮齿类动物中进行了测试。 该实验室和其他实验室将这一结论用作 基本上增加植入的组织的量的基础 临床实验 我们已经能够实现相当高的存活率， 通过研究可能增强它的因素来提高灵长类动物的生存率。 移植物可以从从以下关键阶段获得的组织获得： 多巴胺神经发生 值得注意的是，临床实验 使用的胎龄范围比建议的要大得多 我们的新数据。 此外，我们发现长期服用 左旋多巴在啮齿类动物中导致移植物具有发育不良的多巴胺神经元， 行为改善减少。 其他有关因素 供体组织的制备和储存或药物治疗 在嫁接后可能同样重要。 尽管一些研究表明， 可以提供有用的线索，可以理解， 猴子大脑的复杂性及其与人类大脑的相似性使得 在猴模型中优化移植物的存活率是至关重要的。 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，供体组织如细胞的制备方法 悬液、固体移植物和冷冻保存，以及 常规药物疗法如左旋多巴、丙炔苯丙胺等， 移植物存活率 这些研究将使用以下移植物进行： 在几个时间段内将中脑组织植入猴子， 对于胎龄，悬吊与小实体移植物的匹配比较 植入同一只猴子尾状核的两侧， 新鲜与冷冻保存的组织也被植入在 个脑袋 药理学研究将首先在灵长类动物细胞培养中进行 如果是阳性的，随后的实验将测试这些影响， 猴子 该项目还将检查胚胎移植的有效性， 纹状体以促进来自共同移植的中脑组织的神经突生长 作为一种从移植的神经元中获得更大生长的手段。 期间 在当前的研究期间，我们还发现纹状体移植物 增强对宿主大脑的影响， 酪氨酸羟化酶阳性纤维进入移植物， 背外侧纹状体 我们将从以下几个方面来考察这一现象： 旨在保护残留宿主的早期干预观点 多巴胺能神经元