Enhancing function of grafted primate dopamine neurons

增强移植灵长类多巴胺神经元的功能

• 批准号: 6824642
• 负责人: ROBERT Henry ROTH
• 金额: $ 30.66万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6824642
• 关键词: Cercopithecidae; Parkinson's disease; cell death; disease /disorder model; dopamine; drug delivery systems; embryo /fetus tissue transplantation; histology; nervous system transplantation; neurons; neurotrophic factors; nonhuman therapy evaluation; soma

PROJECT 2. ENHANCING FUNCTION OF GRAFTED PRIMATE DOPAMINE NEURONS WITH NEUROTROPHIC FACTORS The death of the vast majority of transplanted dopamine neurons within the first few days appears to limit the success of this treatment strategy for Parkinson's disease. The inadequacy of critical growth factors in the adult parkinsonian brain may be a major cause of early cell death and restricted outgrowth of grafts placed into the striatum. This project proposes studies to determine whether chronically delivered neurotrophic factors can increase the survival and outgrowth of fetal mesencephatic dopamine neurons, and improve the biochemical and functional outcome of neural grafting in parkinsonian primates. Factors tested will include glial cell line-derived neurotrophic factor (GDNF), delivered biologically by macroencapsulated cells. Fetal striatum releases several neurotrophic factors besides GDNF, and this milieu provides critical support to dopamine neurons during their normal development. Thus, the effect of factors released from fetal striatum enriched in oligodendrocyte-type-2 astrocyte (SO2A) progenitor cells will also be investigated on dopamine neuron survival. Experiments will utilize implantation of GDNF-releasing capsules, or cografting of SO2A cells at increasing distances from ventral mesencephalic grafts placed into the caudate in the MPTP-treated monkey, a model that reproduces all the hallmark behavioral features of Parkinson's disease. Defined dissections of donor tissue and pre-selection of MPTP-treated monkeys will limit variability in the studies. The main end-point measures will be improvement in parkinsonism, correlated with dopamine neuron survival and soma size, and dopamine fiber outgrowth, determined by biochemical measures and light and electron microscopy. Methods for these studies are in place, and key pilot studies strongly support feasibility and the hypotheses. These studies will increase understanding of the interaction of primate fetal dopamine neurons with neurotrophic factors, and will lead to improved and more reproducible methods of cellular replacement which may benefit patients with Parkinson's disease and possibly other neurodegenerative disorders.

项目2。增强移植的灵长类动物多巴胺神经元的功能 与神经营养因素 最初几天内绝大多数移植的多巴胺神经元的死亡似乎限制了这种治疗策略对帕金森氏病的成功。成人帕金森氏症大脑中关键生长因子的不足可能是早期细胞死亡和限制伸入纹状体的移植物生长的主要原因。该项目提出的研究旨在确定慢性传递的神经营养因素是否可以增加胎儿中脑多巴胺神经元的存活和产物，并改善帕金森尼灵长类动物中神经嫁接的生化和功能结果。测试的因素将包括神经胶质细胞衍生的神经营养因子（GDNF），该因子是由大型囊细胞在生物学上传递的。胎儿纹状体除了GDNF以外还释放了几个神经营养因素，并且该环境在正常发育过程中为多巴胺神经元提供了重要的支持。因此， 从多巴胺神经元存活中也研究了富含少突胶质细胞型星形胶质细胞（SO2A）祖细胞的胎儿纹状体释放的因素。实验将利用释放GDNF释放胶囊的植入，或者在与MPTP治疗的猴子中腹侧中脑移植物相距较高的距离内，该模型会重现parkinson疾病的所有标志行为特征。供体组织的定义解剖和MPTP处理的猴子的预选将限制研究中的变异性。主要的终点措施将是帕金森氏症的改善，与多巴胺神经元的存活和SOMA大小相关，以及多巴胺纤维的产物，由生化措施以及光和电子显微镜确定。这些研究的方法已经到位，主要的试点研究强烈支持可行性和假设。这些研究将增加对灵长类胎胎多巴胺神经元与神经营养因素的相互作用的理解，并将领导 为了改善细胞置换的方法，可以使帕金森氏病和其他神经退行性疾病患者受益。