Improving neural graft function in parkinsonian monkeys.

改善帕金森猴的神经移植功能。

• 批准号: 6804952
• 负责人: DONALD EUGENE REDMOND
• 金额: $ 117.98万
• 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/6804952
• 关键词: Parkinson' s disease; dopamine; embryo /fetus tissue transplantation; nervous system transplantation; nonhuman therapy evaluation

The benefits of fetal neural transplantation in primate Parkinson's models have been partially confirmed by studies in patients, but transplantation may have significant problems which should be addressed. Functional improvement appears variable, less effective in older patients, and incomplete in spite of some apparent increases in dopamine production. The hypotheses are that transplantation's limitations result from inadequate grafts, due to poor survival of implanted cells, lack of critical growth factors, or nonphysiological graft placements and distribution. This program proposes to test these hypotheses with strategies which may improve functional benefits--the primary outcome measure of all studies in MPTP parkinsonian monkeys. Project One targets early cell death after grafting, with strategies to reduce oxidant stress, hypoxia/ischemia, and apoptosis using cell adhesion factors, the lazaroid tirilizad mesylate, melatonin, vascular endothelial growth factor, and cAMP. Project Two focuses on growth factors produced by fetal striatum enriched in astrocyte progenitor cells, or the growth factor, GDNF, delivered from encapsulated cells. An optimized method will be tested to determine benefits of combined methods in young adult and aged monkeys. Project Three aims to restore the relevant dopamine pathways by implantation of substantia nigra (SN) precursor tissue into SN and directing its outgrowth to the target areas, using co-grafted fetal striatal cells, or GDNF delivery. Duration of and stability of behavioral improvement, possible dyskinesias, or other toxic effects will be evaluated for three years and compared with striatal grafts. Quantitative behavioral effects will be correlated with biochemical and morphological measurements post-mortem. These studies may contribute to improving graft survival, reinnervation, and physiological restoration of the defective dopamine circuits and normalizing function. Although considerable preliminary work has been done in rodents, and because definitive controlled experiments with verifiable outcomes cannot be accomplished in humans, hypotheses and safety should be tested in the MPTP model in monkeys. The projects will be undertaken jointly by the program investigators, applying the resources of a unique primate transplantation laboratory (Core A) and shared outcome methodologies, all coordinated by a program support unit (Core B). Understanding of fetal precursor cell survival and outgrowth may also lead to improved understanding of the plasticity and function of other potential replacement cells, such as stem cells, and be relevant to other human neurodegenerative or traumatic conditions in addition to Parkinson's disease.

灵长类帕金森病模型中胎儿神经移植的益处已通过患者研究得到部分证实，但移植可能存在应解决的重大问题。尽管多巴胺的产生明显增加，但功能改善似乎存在差异，对老年患者效果较差，而且不完全。假设移植的局限性是由于植入细胞存活率低、缺乏关键生长因子或非生理性移植物放置和分布而造成的移植物不足造成的。该计划提议用可能改善功能益处的策略来测试这些假设——这是所有 MPTP 帕金森猴研究的主要结果指标。 项目一的目标是移植后早期细胞死亡，采用细胞粘附因子、拉齐若得甲磺酸盐、褪黑激素、血管内皮生长因子和 cAMP 来减少氧化应激、缺氧/缺血和细胞凋亡。项目二重点关注富含星形胶质细胞祖细胞的胎儿纹状体产生的生长因子，或从封装细胞传递的生长因子 GDNF。将测试优化的方法，以确定组合方法对年轻成年猴子和老年猴子的益处。项目三旨在 通过将黑质 (SN) 前体组织植入 SN 中并使用共移植胎儿纹状体细胞或 GDNF 递送将其生长引导至目标区域，从而恢复相关的多巴胺通路。将评估行为改善的持续时间和稳定性、可能的运动障碍或其他毒性作用，为期三年，并与纹状体移植物进行比较。定量的行为效应将与生化和 死后形态学测量。这些研究可能有助于改善移植物存活、神经支配、有缺陷的多巴胺回路的生理恢复和功能正常化。尽管在啮齿类动物身上已经做了相当多的初步工作，而且由于无法在人类身上完成具有可验证结果的明确对照实验，所以应该在猴子的 MPTP 模型中测试假设和安全性。这些项目将由项目研究人员联合开展，利用独特的灵长类移植实验室（核心 A）的资源和共享结果方法，所有这些均由项目支持单位（核心 B）协调。对胎儿前体细胞存活和生长的了解也可能有助于更好地了解其他潜在细胞的可塑性和功能 替代细胞，例如干细胞，并且与除帕金森氏病之外的其他人类神经退行性或创伤性疾病相关。